bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating drug repositioning opportunities in FDA drug labels through topic modeling
Authors: Bisgin Halil , Liu Zhichao , Kelly Reagan , Fang Hong , Xu Xiaowei , Tong Weida 
Published: September 2012

Abstract

Background
Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach.

Method
A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels.

Results
Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In addition, we identified two therapeutic groups of drugs (Musculo-skeletal system and Anti-infective for systemic use) where over 80% of the drugs have a potential replacement with high significance.

Conclusion
Topic modeling can be a powerful tool for the identification of repositioning opportunities by examining the adverse event terms in FDA approved drug labels. The proposed framework not only suggests drugs that can be repurposed, but also provides insight into the safety of repositioned drugs.
Metabolic and enzymatic changes associated with carbon mobilization, utilization and replenishment triggered in grain amaranth (Amaranthus cruentus) in response to partial defoliation by mechanical injury or insect herbivory
Authors: Castrillón-Arbeláez Paula Andrea , Martínez-Gallardo Norma , Arnaut Hamlet Avilés , Tiessen Axel , Délano-Frier John Paul 
Published: September 2012

Abstract

Background

Amaranthus cruentus and A. hypochondriacus are crop plants grown for grain production in subtropical countries. Recently, the generation of large-scale transcriptomic data opened the possibility to study representative genes of primary metabolism to gain a better understanding of the biochemical mechanisms underlying tolerance to defoliation in these species. A multi-level approach was followed involving gene expression analysis, enzyme activity and metabolite measurements.

Results
Defoliation by insect herbivory (HD) or mechanical damage (MD) led to a rapid and transient reduction of non-structural carbohydrates (NSC) in all tissues examined. This correlated with a short-term induction of foliar sucrolytic activity, differential gene expression of a vacuolar invertase and its inhibitor, and induction of a sucrose transporter gene. Leaf starch in defoliated plants correlated negatively with amylolytic activity and expression of a β-amylase-1 gene and positively with a soluble starch synthase gene. Fatty-acid accumulation in roots coincided with a high expression of a phosphoenolpyruvate/phosphate transporter gene. In all tissues there was a long-term replenishment of most metabolite pools, which allowed damaged plants to maintain unaltered growth and grain yield. Promoter analysis of ADP-glucose pyrophosphorylase and vacuolar invertase genes indicated the presence of cis-regulatory elements that supported their responsiveness to defoliation. HD and MD had differential effects on transcripts, enzyme activities and metabolites. However, the correlation between transcript abundance and enzymatic activities was very limited. A better correlation was found between enzymes, metabolite levels and growth and reproductive parameters.

Conclusions
It is concluded that a rapid reduction of NSC reserves in leaves, stems and roots followed by their long-term recovery underlies tolerance to defoliation in grain amaranth. This requires the coordinate action of genes/enzymes that are differentially affected by the way leaf damage is performed. Defoliation tolerance in grain is a complex process that can’t be fully explained at the transcriptomic level only.
Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room
Authors: Kung Chia-Te , Hsiao Sheng-Yuan , Tsai Tsung-Cheng , Su Chih-Min , Chang Wen-Neng , Huang Chi-Ren , Wang Hung-Chen , Lin Wei-Che , Chang Hsueh-Wen , Lin Yu-Jun , Cheng Ben-Chung , Su Ben Yu-Jih , Tsai Nai-Wen , Lu Cheng-Hsien 
Published: September 2012

Abstract

Background and aim
The sensitivity and specificity of biomarkers and scoring systems used for predicting fatality of severe sepsis patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating plasma DNA levels in severe septic patients presenting at the Emergency Department (ED).

Methods
Sixty-seven consecutive patients with severe sepsis and 33 controls were evaluated. Plasma DNA levels were estimated by real-time quantitative polymerase chain reaction assay using primers for the human β-hemoglobin and ND2 gene. The patients’ clinical and laboratory data on admission were analyzed.

Results
The median plasma nuclear and mitochondria DNA levels for severe septic patients on admission were significantly higher than those of the controls. The mean plasma nuclear DNA level on admission correlated with lactate concentration (γ = 0.36, p = 0.003) and plasma mitochondrial DNA on admission (γ = 0.708, p < 0.001). Significant prognostic factors for fatality included mechanical ventilation within the first 24 hours (p = 0.013), mean sequential organ failure assessment (SOFA) score on admission (p = 0.04), serum lactate (p < 0.001), and both plasma nuclear and mitochondrial DNA on admission (p < 0.001). Plasma mitochondrial DNA was an independent predictor of fatality by stepwise logistic regression such that an increase by one ng/mL in level would increase fatality rate by 0.7%.

Conclusion
Plasma DNA has potential use for predicting outcome in septic patients arriving at the emergency room. Plasma mitochondrial DNA level on admission is a more powerful predictor than lactate concentration or SOFA scores on admission.
LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors
Authors: Hinkle Kelly M , Yue Mei , Behrouz Bahareh , Dächsel Justus C , Lincoln Sarah J , Bowles Erin E , Beevers Joel E , Dugger Brittany , Winner Beate , Prots Iryna , Kent Caroline B , Nishioka Kenya , Lin Wen-Lang , Dickson Dennis W , Janus Christopher J , Farrer Matthew J , Melrose Heather L 
Published: September 2012

AbstractMutations in theLRRK2gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects ofLRRK2mutations are still not clear, data emerging fromin vitroandin vivomodels suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation.We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis.Our results show that the dopaminergic system was not functionally comprised inLRRK2knockout mice. However,LRRK2knockout mice displayed abnormal exploratory activity in the open-field test. Moreover,LRRK2knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.
URDME: a modular framework for stochastic simulation of reaction-transport processes in complex geometries
Authors: Drawert Brian , Engblom Stefan , Hellander Andreas 
Published: September 2012

Abstract

Background
Experiments in silico using stochastic reaction-diffusion models have emerged as an important tool in molecular systems biology. Designing computational software for such applications poses several challenges. Firstly, realistic lattice-based modeling for biological applications requires a consistent way of handling complex geometries, including curved inner- and outer boundaries. Secondly, spatiotemporal stochastic simulations are computationally expensive due to the fast time scales of individual reaction- and diffusion events when compared to the biological phenomena of actual interest. We therefore argue that simulation software needs to be both computationally efficient, employing sophisticated algorithms, yet in the same time flexible in order to meet present and future needs of increasingly complex biological modeling.

Results
We have developed URDME, a flexible software framework for general stochastic reaction-transport modeling and simulation. URDME uses U nstructured triangular and tetrahedral meshes to resolve general geometries, and relies on the R eaction-D iffusion M aster E quation formalism to model the processes under study. An interface to a mature geometry and mesh handling external software (Comsol Multiphysics) provides for a stable and interactive environment for model construction. The core simulation routines are logically separated from the model building interface and written in a low-level language for computational efficiency. The connection to the geometry handling software is realized via a Matlab interface which facilitates script computing, data management, and post-processing. For practitioners, the software therefore behaves much as an interactive Matlab toolbox. At the same time, it is possible to modify and extend URDME with newly developed simulation routines. Since the overall design effectively hides the complexity of managing the geometry and meshes, this means that newly developed methods may be tested in a realistic setting already at an early stage of development.

Conclusions
In this paper we demonstrate, in a series of examples with high relevance to the molecular systems biology community, that the proposed software framework is a useful tool for both practitioners and developers of spatial stochastic simulation algorithms. Through the combined efforts of algorithm development and improved modeling accuracy, increasingly complex biological models become feasible to study through computational methods. URDME is freely available at http://www.urdme.org.
Interventions in Wnt signaling as a novel therapeutic approach to improve myocardial infarct healing
Authors: Hermans Kevin CM , Daskalopoulos Evangelos P , Blankesteijn W Matthijs 
Published: September 2012

Abstract
Following myocardial infarction, wound healing takes place in the infarct area where the non-viable cardiac tissue is replaced by a scar. Inadequate wound healing or insufficient maintenance of the extracellular matrix in the scar can lead to excessive dilatation of the ventricles, one of the hallmarks of congestive heart failure. Therefore, it is important to better understand the wound-healing process in the heart and to develop new therapeutic agents that target the infarct area in order to maintain an adequate cardiac function. One of these potential novel therapeutic targets is Wnt signaling. Wnt signaling plays an important role in embryonic myocardial development but in the adult heart the pathway is thought to be silent. However, there is increasing evidence that components of the Wnt pathway are re-expressed during cardiac repair, implying a regulatory role. Recently, several studies have been published where the effect of interventions in Wnt signaling on infarct healing has been studied. In this review, we will summarize the results of these studies and discuss the effects of these interventions on the different cell types that are involved in the wound healing process.
Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation
Authors: Lowthert Lori , Leffert Janine , Lin Aiping , Umlauf Sheila , Maloney Kathleen , Muralidharan Anjana , Lorberg Boris , Mane Shrikant , Zhao Hongyu , Sinha Rajita , Bhagwagar Zubin , Beech Robert 
Published: September 2012

Abstract

Background
Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.

Methods
Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.
Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.

Results
127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.

Conclusions
These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.
Doppler resistive index to reflect regulation of renal vascular tone during sepsis and acute kidney injury
Authors: Dewitte Antoine , Coquin Julien , Meyssignac Bertrand , Joannès-Boyau Olivier , Fleureau Catherine , Roze Hadrien , Ripoche Jean , Janvier Gérard , Combe Christian , Ouattara Alexandre 
Published: September 2012

Abstract
Introduction
Renal resistive index (RI), determined by Doppler ultrasonography, directly reveals and quantifies modifications in renal vascular resistance. The aim of this study was to evaluate if mean arterial pressure (MAP) is determinant of renal RI in septic, critically ill patients suffering or not from acute kidney injury (AKI).

Methods
This prospective observational study included 96 patients. AKI was defined according to RIFLE criteria and transient or persistent AKI according to renal recovery within 3 days.

Results
Median renal RIs were 0.72 (0.68-0.75) in patients without AKI and 0.76 (0.72-0.80) in patients with AKI (P=0.001). RIs were 0.75 (0.72-0.79) in transient AKI and 0.77 (0.70-0.80) in persistent AKI (P=0.84). RI did not differ in patients given norepinephrine infusion and was not correlated with norepinephrine dose. RI was correlated with MAP (ρ= -0.47; P=0.002), PaO2/FiO2 ratio (ρ= -0.33; P=0.04) and age (ρ=0.35; P=0.015) only in patients without AKI.

Conclusions
A poor correlation between renal RI and MAP, age, or PaO2/FiO2 ratio was found in septic and critically ill patients without AKI compared to patients with AKI. These findings suggest that determinants of RI are multiple. Renal circulatory response to sepsis estimated by Doppler ultrasonography cannot reliably be predicted simply from changes in systemic hemodynamics. As many factors influence its value, the interest in a single RI measurement at ICU admission to determine optimal MAP remains uncertain.
Migration of Cells from Experimental Endometriosis to the Uterine Endometrium
Authors: Santamaria Xavier , Massasa Efi E. , Taylor Hugh S. 
Published: September 2012

Abstract
Endometriosis is the estrogen-dependent growth of endometrial tissue outside the uterus. Endometriosis has an effect on the eutopic endometrium; however, the nature of the cellular or molecular signal from the lesion to the uterus is unknown. Here we demonstrate that cells migrate from endometriosis to eutopic endometrium. Experimental endometriosis was established by transplanting endometrial tissue from green fluorescent protein (GFP) mice to the peritoneal cavity of DS-Red mice. Immunofluorescence (IF) identified cells from the ectopic lesions in the uterus. The eutopic endometrial cells were sorted by fluorescence activated cell sorting, and the GFP+/DS-Red− population was characterized using microarray analysis. The results of cell sorting as well as the array results were confirmed by quantitative PCR and IF. GFP+/DS-red−/Cd45− cells were identified in the eutopic endometrium of mice with experimental endometriois (∼1.8%) and not in controls. Global gene expression profiling of these cells showed absence of leukocyte and increased expression of pan-epithelial markers in the uterine GFP+ cells. Moreover, GFP+ cells showed up-regulation of Wnt7A expression and 17 other genes associated with the Wingless pathway. Several genes that are associated with epithelial-to-mesenchymal transition were also highly differentially expressed in GFP+ cells. IF confirmed the presence of the GFP+/CD45−/Wnt7a+/cytokeritin+ cells in the endometrium of endometriotic animals, and not in controls. Cells from endometriotic lesions are capable of migrating to the eutopic endometrium. The ectopic expression of Wnt7A suggests a possible mechanism by which ectopic lesions affect the eutopic endometrium and interfere with embryo implantation and fertility.
Doctors' age at domestic partnership and parenthood: cohort studies
Authors: Goldacre Michael J , Davidson Jean M , Lambert Trevor W 
Published: September 2012

Objective To report on doctors’ family formation. Design Cohort studies using structured questionnaires. Setting UK. Participants Doctors who qualified in 1988, 1993, 1996, 1999, 2000 and 2002 were followed up. Main Outcome Measures Living with spouse or partner; and doctors’ age when first child was born. Results The response to surveys including questions about domestic circumstances was 89.8% (20,717/23,077 doctors). The main outcomes – living with spouse or partner, and parenthood – varied according to age at qualification. Using the modal ages of 23–24 years at qualification, by the age of 24–25 (i.e. in their first year of medical work) a much smaller percentage of doctors than the general population was living with spouse or partner. By the age of 33, 75% of both women and men doctors were living with spouse or partner, compared with 68% of women and 61% of men aged 33 in the general population. By the age of 24–25, 2% of women doctors and 41% of women in the general population had a child; but women doctors caught up with the general population, in this respect, in their 30s. The specialty with the highest percentage of women doctors who, aged 35, had children was general practice (74%); the lowest was surgery (41%). Conclusions Doctors are more likely than other people to live with a spouse or partner, and to have children, albeit typically at later ages. Differences between specialties in rates of motherhood may indicate sacrifice by some women of family in favour of career.
The Effect of Information Technology–Enabled Flexibility on Formation and Market Value of Alliances
Authors: Tafti Ali , Mithas Sunil , Krishnan M. S. 
Published: September 2012

This study investigates the effect of information technology (IT) architecture flexibility on strategic alliance formation and firm value. We first examine the effect of three dimensions of IT architecture flexibility (open communication standards, cross-functional transparency, and modularity) on formation of three types of alliances (arm's-length, collaborative, and joint-venture alliances, respectively). Then, we examine how capabilities in IT flexibility can enhance the value derived from alliances. Our sample includes data from 169 firms that are publicly listed in the United States and that span multiple industries. We find that adoption of open communication standards is associated with the formation of arm's-length alliances, and modularity of IT architecture is associated with the formation of joint ventures. We also find that IT architecture flexibility enhances the value of arm's-length, collaborative, and joint-venture alliances. The contribution of IT flexibility to value is greater in the case of collaborative alliances than in arm's-length alliances. Taken together, these findings suggest that appropriate investments in IT can help to facilitate reconfiguration of resources and modification of processes in collaboration-intensive alliances. This paper was accepted by Ramayya Krishnan, information systems.
ELF authentication and accommodation strategies in crosscultural immigration encounters
Authors: Guido, Maria Grazia 
Published: September 2012

Abstract
This article explores the cognitive and communicative strategies involved in the use of ELF in situations of unequal encounters between non-western supplicants (i.e., African immigrants and asylum seekers) and western immigration officials in authority (in this case, Italian mediators – i.e., experts mediating between immigrants and institutions). Evidence from the case studies indicates that each contact group uses ELF with reference to different linguacultural conventions associated with their use of English, as the interactants come from the ‘outer’ and the ‘expanding’ circles respectively (cf. Kachru 1986). In consequence, each party in the encounters tends naturally to transfer the structural features and the meaning conventions of their L1 into the English that they use, each appropriating and “authenticating” the language in accordance not with native speaker norms, but with those of their own L1. Since these norms are not shared, there is the need for accommodation for communication to be achieved, but unequal power distribution in these encounters is not favorable to such accommodation – which, instead, normally obtains in relatively “equal” encounters. The case studies show how the lack of recognition of these variable versions of English may have critical consequences in contexts involving political and ethical questions concerning human rights. It is contended that only a “mutual accommodation” of variable usage would safeguard the participants' social identities and foster successful communication in crosscultural immigration encounters.