New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells.

PubMed

Heinrich, Jörg C; Donakonda, Sainitin; Haupt, V Joachim; Lennig, Petra; Zhang, Yixin; Schroeder, Michael

2016-10-18

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.

eRepo-ORP: Exploring the Opportunity Space to Combat Orphan Diseases with Existing Drugs.

PubMed

Brylinski, Michal; Naderi, Misagh; Govindaraj, Rajiv Gandhi; Lemoine, Jeffrey

2017-12-10

About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Here, we present eRepo-ORP, a comprehensive resource constructed by a large-scale repositioning of existing drugs to orphan diseases with a collection of structural bioinformatics tools, including eThread, eFindSite, and eMatchSite. Specifically, a systematic exploration of 320,856 possible links between known drugs in DrugBank and orphan proteins obtained from Orphanet reveals as many as 18,145 candidates for repurposing. In order to illustrate how potential therapeutics for rare diseases can be identified with eRepo-ORP, we discuss the repositioning of a kinase inhibitor for Ras-associated autoimmune leukoproliferative disease. The eRepo-ORP data set is available through the Open Science Framework at https://osf.io/qdjup/. Copyright © 2017. Published by Elsevier Ltd.

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease.

PubMed

Shameer, Khader; Dow, Garrett; Glicksberg, Benjamin S; Johnson, Kipp W; Ze, Yi; Tomlinson, Max S; Readhead, Ben; Dudley, Joel T; Kullo, Iftikhar J

2018-01-01

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease.

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease

PubMed Central

Shameer, Khader; Dow, Garrett; Glicksberg, Benjamin S.; Johnson, Kipp W.; Ze, Yi; Tomlinson, Max S.; Readhead, Ben; Dudley, Joel T.; Kullo, Iftikhar J.

2018-01-01

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease. PMID:29888052

A physarum-inspired prize-collecting steiner tree approach to identify subnetworks for drug repositioning.

PubMed

Sun, Yahui; Hameed, Pathima Nusrath; Verspoor, Karin; Halgamuge, Saman

2016-12-05

Drug repositioning can reduce the time, costs and risks of drug development by identifying new therapeutic effects for known drugs. It is challenging to reposition drugs as pharmacological data is large and complex. Subnetwork identification has already been used to simplify the visualization and interpretation of biological data, but it has not been applied to drug repositioning so far. In this paper, we fill this gap by proposing a new Physarum-inspired Prize-Collecting Steiner Tree algorithm to identify subnetworks for drug repositioning. Drug Similarity Networks (DSN) are generated using the chemical, therapeutic, protein, and phenotype features of drugs. In DSNs, vertex prizes and edge costs represent the similarities and dissimilarities between drugs respectively, and terminals represent drugs in the cardiovascular class, as defined in the Anatomical Therapeutic Chemical classification system. A new Physarum-inspired Prize-Collecting Steiner Tree algorithm is proposed in this paper to identify subnetworks. We apply both the proposed algorithm and the widely-used GW algorithm to identify subnetworks in our 18 generated DSNs. In these DSNs, our proposed algorithm identifies subnetworks with an average Rand Index of 81.1%, while the GW algorithm can only identify subnetworks with an average Rand Index of 64.1%. We select 9 subnetworks with high Rand Index to find drug repositioning opportunities. 10 frequently occurring drugs in these subnetworks are identified as candidates to be repositioned for cardiovascular diseases. We find evidence to support previous discoveries that nitroglycerin, theophylline and acarbose may be able to be repositioned for cardiovascular diseases. Moreover, we identify seven previously unknown drug candidates that also may interact with the biological cardiovascular system. These discoveries show our proposed Prize-Collecting Steiner Tree approach as a promising strategy for drug repositioning.

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

PubMed Central

Lennig, Petra; Zhang, Yixin; Schroeder, Michael

2016-01-01

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads – chlorpromazine – is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning. PMID:27626687

Mining drug-disease relationships as a complement to medical genetics-based drug repositioning: Where a recommendation system meets genome-wide association studies.

PubMed

Wang, H; Gu, Q; Wei, J; Cao, Z; Liu, Q

2015-05-01

A novel recommendation-based drug repositioning strategy is presented to simultaneously determine novel drug indications and side effects in one integrated framework. This strategy provides a complementary method to medical genetics-based drug repositioning, which reduces the occurrence of false positives in medical genetics-based drug repositioning, resulting in a ranked list of new candidate indications and/or side effects with different confidence levels. Several new drug indications and side effects are reported with high prediction confidences. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Drug Repositioning for Gynecologic Tumors: A New Therapeutic Strategy for Cancer

PubMed Central

Banno, Kouji; Yanokura, Megumi; Irie, Haruko; Masuda, Kenta; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

2015-01-01

The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery. PMID:25734181

Drug repositioning summit: finding new routes to success.

PubMed

Campas, Clara

2009-03-01

The Third Annual Drug Repositioning Summit 2008 was held at the Hyatt Harborside Hotel in Boston, Massachusetts, October 6-7, and focused on new strategies for drug repositioning. The meeting, organized by The Cambridge Healthtech Institute, brought together a panel of speakers from the industry and the academia, who discussed and proposed new routes for success in drug repositioning based on their own experience in the field. This meeting report summarizes the most relevant presentations and issues discussed. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Predicting New Indications for Approved Drugs Using a Proteo-Chemometric Method

PubMed Central

Dakshanamurthy, Sivanesan; Issa, Naiem T; Assefnia, Shahin; Seshasayee, Ashwini; Peters, Oakland J; Madhavan, Subha; Uren, Aykut; Brown, Milton L; Byers, Stephen W

2012-01-01

The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chemical screening, transcriptome matching or simple in silico ligand docking. We now describe a novel rapid computational proteo-chemometric method called “Train, Match, Fit, Streamline” (TMFS) to map new drug-target interaction space and predict new uses. The TMFS method combines shape, topology and chemical signatures, including docking score and functional contact points of the ligand, to predict potential drug-target interactions with remarkable accuracy. Using the TMFS method, we performed extensive molecular fit computations on 3,671 FDA approved drugs across 2,335 human protein crystal structures. The TMFS method predicts drug-target associations with 91% accuracy for the majority of drugs. Over 58% of the known best ligands for each target were correctly predicted as top ranked, followed by 66%, 76%, 84% and 91% for agents ranked in the top 10, 20, 30 and 40, respectively, out of all 3,671 drugs. Drugs ranked in the top 1–40, that have not been experimentally validated for a particular target now become candidates for repositioning. Furthermore, we used the TMFS method to discover that mebendazole, an anti-parasitic with recently discovered and unexpected anti-cancer properties, has the structural potential to inhibit VEGFR2. We confirmed experimentally that mebendazole inhibits VEGFR2 kinase activity as well as angiogenesis at doses comparable with its known effects on hookworm. TMFS also predicted, and was confirmed with surface plasmon resonance, that dimethyl celecoxib and the anti-inflammatory agent celecoxib can bind cadherin-11, an adhesion molecule important in rheumatoid arthritis and poor prognosis malignancies for which no targeted therapies exist. We anticipate that expanding our TMFS method to the >27,000 clinically active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets. PMID:22780961

Drug repositioning for enzyme modulator based on human metabolite-likeness.

PubMed

Lee, Yoon Hyeok; Choi, Hojae; Park, Seongyong; Lee, Boah; Yi, Gwan-Su

2017-05-31

Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.

Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events.

PubMed

Wang, Kejian; Wan, Mei; Wang, Rui-Sheng; Weng, Zuquan

2016-04-01

Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning.

The functional therapeutic chemical classification system.

PubMed

Croset, Samuel; Overington, John P; Rebholz-Schuhmann, Dietrich

2014-03-15

Drug repositioning is the discovery of new indications for compounds that have already been approved and used in a clinical setting. Recently, some computational approaches have been suggested to unveil new opportunities in a systematic fashion, by taking into consideration gene expression signatures or chemical features for instance. We present here a novel method based on knowledge integration using semantic technologies, to capture the functional role of approved chemical compounds. In order to computationally generate repositioning hypotheses, we used the Web Ontology Language to formally define the semantics of over 20 000 terms with axioms to correctly denote various modes of action (MoA). Based on an integration of public data, we have automatically assigned over a thousand of approved drugs into these MoA categories. The resulting new resource is called the Functional Therapeutic Chemical Classification System and was further evaluated against the content of the traditional Anatomical Therapeutic Chemical Classification System. We illustrate how the new classification can be used to generate drug repurposing hypotheses, using Alzheimers disease as a use-case. https://www.ebi.ac.uk/chembl/ftc; https://github.com/loopasam/ftc. croset@ebi.ac.uk Supplementary data are available at Bioinformatics online.

Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine.

PubMed

Kim, Jihye; Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kang, Jaewoo; Tan, Aik Choon

2018-01-01

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis.

Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine

PubMed Central

Kim, Jihye; Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kang, Jaewoo

2018-01-01

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis. PMID:29765977

Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases.

PubMed

Williams, Kevin; Bilsland, Elizabeth; Sparkes, Andrew; Aubrey, Wayne; Young, Michael; Soldatova, Larisa N; De Grave, Kurt; Ramon, Jan; de Clare, Michaela; Sirawaraporn, Worachart; Oliver, Stephen G; King, Ross D

2015-03-06

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist 'Eve' designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.

Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases

PubMed Central

Williams, Kevin; Bilsland, Elizabeth; Sparkes, Andrew; Aubrey, Wayne; Young, Michael; Soldatova, Larisa N.; De Grave, Kurt; Ramon, Jan; de Clare, Michaela; Sirawaraporn, Worachart; Oliver, Stephen G.; King, Ross D.

2015-01-01

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax. PMID:25652463

Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning

PubMed Central

Kaiser, Marcel; Mäser, Pascal; Tadoori, Leela Pavan; Ioset, Jean-Robert; Brun, Reto

2015-01-01

Neglected tropical diseases cause significant morbidity and mortality and are a source of poverty in endemic countries. Only a few drugs are available to treat diseases such as leishmaniasis, Chagas’ disease, human African trypanosomiasis and malaria. Since drug development is lengthy and expensive, a drug repurposing strategy offers an attractive fast-track approach to speed up the process. A set of 100 registered drugs with drug repositioning potential for neglected diseases was assembled and tested in vitro against four protozoan parasites associated with the aforementioned diseases. Several drugs and drug classes showed in vitro activity in those screening assays. The results are critically reviewed and discussed in the perspective of a follow-up drug repositioning strategy where R&D has to be addressed with limited resources. PMID:26270335

Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome.

PubMed

Chatterjee, Paulami; Roy, Debjani; Rathi, Nitin

2018-01-01

Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. The findings of our work might provide insight into future AD epigenetic-therapeutics.

Drug repositioning: playing dirty to kill pain.

PubMed

Bastos, Leandro Francisco Silva; Coelho, Márcio Matos

2014-01-01

The number of approved new molecular entity drugs has been decreasing as the pharmaceutical company investment in research and development is increasing. As we face this painful crisis, called an innovation gap, there is increasing awareness that development of new uses of existing drugs may be a powerful tool to help overcome this obstacle because it takes too long, costs too much and can be risky to release drugs developed de novo. Consequently, drug repositioning is emerging in different therapeutic areas, including the pain research area. Worldwide, pain is the main reason for seeking healthcare, and pain relief represents an unmet global clinical need. Therefore, development of analgesics with better efficacy, safety and cost effectiveness is of paramount importance. Despite the remarkable advancement in research on cellular and molecular mechanisms underlying pain pathophysiology over the past three decades, target-based therapeutic opportunities have not been pursued to the same extent. Phenotypic screening remains a more powerful tool for drug development than target-based screening so far. It sounds somewhat heretical, but some multi-action drugs, rather than very selective ones, have been developed intentionally. In the present review, we first critically discuss the utility of drug repositioning for analgesic drug development and then show examples of 'old' drugs that have been successfully repositioned or that are under investigation for their analgesic actions. We conclude that drug repositioning should be more strongly encouraged to help build a bridge between basic research and pain relief worldwide.

Repositioning drugs for inflammatory disease – fishing for new anti-inflammatory agents

PubMed Central

Hall, Christopher J.; Wicker, Sophie M.; Chien, An-Tzu; Tromp, Alisha; Lawrence, Lisa M.; Sun, Xueying; Krissansen, Geoffrey W.; Crosier, Kathryn E.; Crosier, Philip S.

2014-01-01

Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs. PMID:25038060

DPDR-CPI, a server that predicts Drug Positioning and Drug Repositioning via Chemical-Protein Interactome.

PubMed

Luo, Heng; Zhang, Ping; Cao, Xi Hang; Du, Dizheng; Ye, Hao; Huang, Hui; Li, Can; Qin, Shengying; Wan, Chunling; Shi, Leming; He, Lin; Yang, Lun

2016-11-02

The cost of developing a new drug has increased sharply over the past years. To ensure a reasonable return-on-investment, it is useful for drug discovery researchers in both industry and academia to identify all the possible indications for early pipeline molecules. For the first time, we propose the term computational "drug candidate positioning" or "drug positioning", to describe the above process. It is distinct from drug repositioning, which identifies new uses for existing drugs and maximizes their value. Since many therapeutic effects are mediated by unexpected drug-protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles to predict indications. Here we introduce the server DPDR-CPI, which can make real-time predictions based only on the structure of the small molecule. When a user submits a molecule, the server will dock it across 611 human proteins, generating a CPI profile of features that can be used for predictions. It can suggest the likelihood of relevance of the input molecule towards ~1,000 human diseases with top predictions listed. DPDR-CPI achieved an overall AUROC of 0.78 during 10-fold cross-validations and AUROC of 0.76 for the independent validation. The server is freely accessible via http://cpi.bio-x.cn/dpdr/.

Drug Repositioning for Effective Prostate Cancer Treatment.

PubMed

Turanli, Beste; Grøtli, Morten; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Arga, Kazim Y; Mardinoglu, Adil

2018-01-01

Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds.

PubMed

Würth, Roberto; Thellung, Stefano; Bajetto, Adriana; Mazzanti, Michele; Florio, Tullio; Barbieri, Federica

2016-01-01

Drug repositioning is gaining increasing attention in drug discovery because it represents a smart way to exploit new molecular targets of a known drug or target promiscuity among diverse diseases, for medical uses different from the one originally considered. In this review, we focus on known non-oncological drugs with new therapeutic applications in oncology, explaining the rationale behind this approach and providing practical evidence. Moving from incompleteness of the knowledge of drug-target interactions, particularly for older molecules, we highlight opportunities for repurposing compounds as cancer therapeutics, underling the biologically and clinically relevant affinities for new targets. Ideal candidates for repositioning can contribute to the therapeutically unmet need for more-efficient anticancer agents, including drugs that selectively target cancer stem cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bioinformatics in translational drug discovery.

PubMed

Wooller, Sarah K; Benstead-Hume, Graeme; Chen, Xiangrong; Ali, Yusuf; Pearl, Frances M G

2017-08-31

Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated during all phases of drug discovery is enabling key challenges of the process to be addressed. Here, we highlight some of the areas in which bioinformatics resources and methods are being developed to support the drug discovery pipeline. These include the creation of large data warehouses, bioinformatics algorithms to analyse 'big data' that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and prediction of repositioning opportunities that use licensed drugs to treat additional indications. © 2017 The Author(s).

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov.

PubMed

Su, Eric Wen; Sanger, Todd M

2017-01-01

Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer).

Literature-based prediction of novel drug indications considering relationships between entities.

PubMed

Jang, Giup; Lee, Taekeon; Lee, Byung Mun; Yoon, Youngmi

2017-06-27

There have been many attempts to identify and develop new uses for existing drugs, which is known as drug repositioning. Among these efforts, text mining is an effective means of discovering novel knowledge from a large amount of literature data. We identify a gene regulation by a drug and a phenotype based on the biomedical literature. Drugs or phenotypes can activate or inhibit gene regulation. We calculate the therapeutic possibility that a drug acts on a phenotype by means of these two types of regulation. We assume that a drug treats a phenotype if the genes regulated by the phenotype are inversely correlated with the genes regulated by the drug. Based on this hypothesis, we identify drug-phenotype associations with therapeutic possibility. To validate the drug-phenotype associations predicted by our method, we make an enrichment comparison with known drug-phenotype associations. We also identify candidate drugs for drug repositioning from novel associations and thus reveal that our method is a novel approach to drug repositioning.

[Drug Repositioning Research Utilizing a Large-scale Medical Claims Database to Improve Survival Rates after Cardiopulmonary Arrest].

PubMed

Zamami, Yoshito; Niimura, Takahiro; Takechi, Kenshi; Imanishi, Masaki; Koyama, Toshihiro; Ishizawa, Keisuke

2017-01-01

 Approximately 100000 people suffer cardiopulmonary arrest in Japan every year, and the aging of society means that this number is expected to increase. Worldwide, approximately 100 million develop cardiac arrest annually, making it an international issue. Although survival has improved thanks to advances in cardiopulmonary resuscitation, there is a high rate of postresuscitation encephalopathy after the return of spontaneous circulation, and the proportion of patients who can return to normal life is extremely low. Treatment for postresuscitation encephalopathy is long term, and if sequelae persist then nursing care is required, causing immeasurable economic burdens as a result of ballooning medical costs. As at present there is no drug treatment to improve postresuscitation encephalopathy as a complication of cardiopulmonary arrest, the development of novel drug treatments is desirable. In recent years, new efficacy for existing drugs used in the clinical setting has been discovered, and drug repositioning has been proposed as a strategy for developing those drugs as therapeutic agents for different diseases. This review describes a large-scale database study carried out following a discovery strategy for drug repositioning with the objective of improving survival rates after cardiopulmonary arrest and discusses future repositioning prospects.

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase.

PubMed

Segura-Cabrera, Aldo; Tripathi, Reshmi; Zhang, Xiaoyi; Gui, Lin; Chou, Tsui-Fen; Komurov, Kakajan

2017-03-21

Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

Towards precision medicine-based therapies for glioblastoma: interrogating human disease genomics and mouse phenotypes.

PubMed

Chen, Yang; Gao, Zhen; Wang, Bingcheng; Xu, Rong

2016-08-22

Glioblastoma (GBM) is the most common and aggressive brain tumors. It has poor prognosis even with optimal radio- and chemo-therapies. Since GBM is highly heterogeneous, drugs that target on specific molecular profiles of individual tumors may achieve maximized efficacy. Currently, the Cancer Genome Atlas (TCGA) projects have identified hundreds of GBM-associated genes. We develop a drug repositioning approach combining disease genomics and mouse phenotype data towards predicting targeted therapies for GBM. We first identified disease specific mouse phenotypes using the most recently discovered GBM genes. Then we systematically searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with GBM. We evaluated the ranks for approved and novel GBM drugs, and compared with an existing approach, which also use the mouse phenotype data but not the disease genomics data. We achieved significantly higher ranks for the approved and novel GBM drugs than the earlier approach. For all positive examples of GBM drugs, we achieved a median rank of 9.2 45.6 of the top predictions have been demonstrated effective in inhibiting the growth of human GBM cells. We developed a computational drug repositioning approach based on both genomic and phenotypic data. Our approach prioritized existing GBM drugs and outperformed a recent approach. Overall, our approach shows potential in discovering new targeted therapies for GBM.

EMUDRA: Ensemble of Multiple Drug Repositioning Approaches to Improve Prediction Accuracy.

PubMed

Zhou, Xianxiao; Wang, Minghui; Katsyv, Igor; Irie, Hanna; Zhang, Bin

2018-04-24

Availability of large-scale genomic, epigenetic and proteomic data in complex diseases makes it possible to objectively and comprehensively identify therapeutic targets that can lead to new therapies. The Connectivity Map has been widely used to explore novel indications of existing drugs. However, the prediction accuracy of the existing methods, such as Kolmogorov-Smirnov statistic remains low. Here we present a novel high-performance drug repositioning approach that improves over the state-of-the-art methods. We first designed an expression weighted cosine method (EWCos) to minimize the influence of the uninformative expression changes and then developed an ensemble approach termed EMUDRA (Ensemble of Multiple Drug Repositioning Approaches) to integrate EWCos and three existing state-of-the-art methods. EMUDRA significantly outperformed individual drug repositioning methods when applied to simulated and independent evaluation datasets. We predicted using EMUDRA and experimentally validated an antibiotic rifabutin as an inhibitor of cell growth in triple negative breast cancer. EMUDRA can identify drugs that more effectively target disease gene signatures and will thus be a useful tool for identifying novel therapies for complex diseases and predicting new indications for existing drugs. The EMUDRA R package is available at doi:10.7303/syn11510888. bin.zhang@mssm.edu or zhangb@hotmail.com. Supplementary data are available at Bioinformatics online.

An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method.

PubMed

Lara-Ramirez, Edgar E; López-Cedillo, Julio Cesar; Nogueda-Torres, Benjamin; Kashif, Muhammad; Garcia-Perez, Carlos; Bocanegra-Garcia, Virgilio; Agusti, Rosalía; Uhrig, María Laura; Rivera, Gildardo

2017-05-26

Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion-exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti-hypertensive, and antibiotic properties showed better trypanocidal effects (LC 50 range = 4.5-25.8 μg/mL) than the reference drugs, nifurtimox and benznidazole (LC 50 range = 36.1-46.8 μg/mL) in both strains in the in vitro model. The anti-inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Assessment of berberine as a multi-target antimicrobial: a multi-omics study for drug discovery and repositioning.

PubMed

Karaosmanoglu, Kubra; Sayar, Nihat Alpagu; Kurnaz, Isil Aksan; Akbulut, Berna Sariyar

2014-01-01

Postgenomics drug development is undergoing major transformation in the age of multi-omics studies and drug repositioning. Rather than applications solely in personalized medicine, omics science thus additionally offers a better understanding of a broader range of drug targets and drug repositioning. Berberine is an isoquinoline alkaloid found in many medicinal plants. We report here a whole genome microarray study in tandem with proteomics techniques for mining the plethora of targets that are putatively involved in the antimicrobial activity of berberine against Escherichia coli. We found DNA replication/repair and transcription to be triggered by berberine, indicating that nucleic acids, in general, are among its targets. Our combined transcriptomics and proteomics multi-omics findings underscore that, in the presence of berberine, cell wall or cell membrane transport and motility-related functions are also specifically regulated. We further report a general decline in metabolism, as seen by repression of genes in carbohydrate and amino acid metabolism, energy production, and conversion. An involvement of multidrug efflux pumps, as well as reduced membrane permeability for developing resistance against berberine in E. coli was noted. Collectively, these findings offer original and significant leads for omics-guided drug discovery and future repositioning approaches in the postgenomics era, using berberine as a multi-omics case study.

Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning

NASA Astrophysics Data System (ADS)

Alberca, Lucas N.; Sbaraglini, María L.; Balcazar, Darío; Fraccaroli, Laura; Carrillo, Carolina; Medeiros, Andrea; Benitez, Diego; Comini, Marcelo; Talevi, Alan

2016-04-01

Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids ( T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.

A cross-species analysis method to analyze animal models' similarity to human's disease state

PubMed Central

2012-01-01

Background Animal models are indispensable tools in studying the cause of human diseases and searching for the treatments. The scientific value of an animal model depends on the accurate mimicry of human diseases. The primary goal of the current study was to develop a cross-species method by using the animal models' expression data to evaluate the similarity to human diseases' and assess drug molecules' efficiency in drug research. Therefore, we hoped to reveal that it is feasible and useful to compare gene expression profiles across species in the studies of pathology, toxicology, drug repositioning, and drug action mechanism. Results We developed a cross-species analysis method to analyze animal models' similarity to human diseases and effectiveness in drug research by utilizing the existing animal gene expression data in the public database, and mined some meaningful information to help drug research, such as potential drug candidates, possible drug repositioning, side effects and analysis in pharmacology. New animal models could be evaluated by our method before they are used in drug discovery. We applied the method to several cases of known animal model expression profiles and obtained some useful information to help drug research. We found that trichostatin A and some other HDACs could have very similar response across cell lines and species at gene expression level. Mouse hypoxia model could accurately mimic the human hypoxia, while mouse diabetes drug model might have some limitation. The transgenic mouse of Alzheimer was a useful model and we deeply analyzed the biological mechanisms of some drugs in this case. In addition, all the cases could provide some ideas for drug discovery and drug repositioning. Conclusions We developed a new cross-species gene expression module comparison method to use animal models' expression data to analyse the effectiveness of animal models in drug research. Moreover, through data integration, our method could be applied for drug research, such as potential drug candidates, possible drug repositioning, side effects and information about pharmacology. PMID:23282076

A cross-species analysis method to analyze animal models' similarity to human's disease state.

PubMed

Yu, Shuhao; Zheng, Lulu; Li, Yun; Li, Chunyan; Ma, Chenchen; Li, Yixue; Li, Xuan; Hao, Pei

2012-01-01

Animal models are indispensable tools in studying the cause of human diseases and searching for the treatments. The scientific value of an animal model depends on the accurate mimicry of human diseases. The primary goal of the current study was to develop a cross-species method by using the animal models' expression data to evaluate the similarity to human diseases' and assess drug molecules' efficiency in drug research. Therefore, we hoped to reveal that it is feasible and useful to compare gene expression profiles across species in the studies of pathology, toxicology, drug repositioning, and drug action mechanism. We developed a cross-species analysis method to analyze animal models' similarity to human diseases and effectiveness in drug research by utilizing the existing animal gene expression data in the public database, and mined some meaningful information to help drug research, such as potential drug candidates, possible drug repositioning, side effects and analysis in pharmacology. New animal models could be evaluated by our method before they are used in drug discovery. We applied the method to several cases of known animal model expression profiles and obtained some useful information to help drug research. We found that trichostatin A and some other HDACs could have very similar response across cell lines and species at gene expression level. Mouse hypoxia model could accurately mimic the human hypoxia, while mouse diabetes drug model might have some limitation. The transgenic mouse of Alzheimer was a useful model and we deeply analyzed the biological mechanisms of some drugs in this case. In addition, all the cases could provide some ideas for drug discovery and drug repositioning. We developed a new cross-species gene expression module comparison method to use animal models' expression data to analyse the effectiveness of animal models in drug research. Moreover, through data integration, our method could be applied for drug research, such as potential drug candidates, possible drug repositioning, side effects and information about pharmacology.

Drug repurposing: translational pharmacology, chemistry, computers and the clinic.

PubMed

Issa, Naiem T; Byers, Stephen W; Dakshanamurthy, Sivanesan

2013-01-01

The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures. Although this approach is hypothesis-driven, the actual success has been very low, contributing to the soaring costs of research and development as well as the diminished pharmaceutical pipeline in the United States. In this review, we discuss the evolution in computational pharmacology as the next generation of successful drug discovery and implementation in the clinic where high-performance computing (HPC) is used to generate and validate drug-target-effect hypotheses completely in silico. The use of HPC would decrease development time and errors while increasing productivity prior to in vitro, animal and human testing. We highlight approaches in chemoinformatics, bioinformatics as well as network biopharmacology to illustrate potential avenues from which to design clinically efficacious drugs. We further discuss the implications of combining these approaches into an integrative methodology for high-accuracy computational predictions within the context of drug repositioning for the efficient streamlining of currently approved drugs back into clinical trials for possible new indications.

The A-Z of Zika drug discovery.

PubMed

Mottin, Melina; Borba, Joyce V V B; Braga, Rodolpho C; Torres, Pedro H M; Martini, Matheus C; Proenca-Modena, Jose Luiz; Judice, Carla C; Costa, Fabio T M; Ekins, Sean; Perryman, Alexander L; Andrade, Carolina Horta

2018-06-20

Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond. Copyright © 2018. Published by Elsevier Ltd.

Applications and Implications of Heparin and Protamine in Tissue Engineering and Regenerative Medicine

PubMed Central

Nemeno, Judee Grace E.; Lee, Kyung Mi

2014-01-01

Drug repositioning is one of the most rapidly emerging fields of study. This concept is anchored on the principle that diseases have similar damaged or affected signaling pathways. Recently, drugs have been repositioned not only for their alternative therapeutic uses but also for their applications as biomaterials in various fields. However, medical drugs as biomaterials are rarely focused on in reviews. Fragmin and protamine have been recently the sources of increasing attention in the field of tissue engineering and regenerative medicine. Fragmin and protamine have been manufactured primarily as a safe antidote for the circulating heparin. Lately, these drugs have been utilized as either micro- or nanoparticle biomaterials. In this paper, we will briefly describe the concept of drug repositioning and some of the medical drugs that have been repurposed for their alternative therapeutic uses. Also, this will feature the historical background of the studies focused on fragmin/protamine micro/nanoparticles (F/P M/NPs) and their applications as biomaterials in tissue engineering, stem cell therapy, and regenerative medicine. PMID:24995338

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies.

PubMed

Palos, Isidro; Lara-Ramirez, Edgar E; Lopez-Cedillo, Julio Cesar; Garcia-Perez, Carlos; Kashif, Muhammad; Bocanegra-Garcia, Virgilio; Nogueda-Torres, Benjamin; Rivera, Gildardo

2017-06-18

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi , which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC 50 range 15.8-26.1 μg/mL) in comparison with benznidazole and nifurtimox (LC 50 range 33.1-46.7 μg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90-60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

Pharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump Inhibitors.

PubMed

Astolfi, Andrea; Felicetti, Tommaso; Iraci, Nunzio; Manfroni, Giuseppe; Massari, Serena; Pietrella, Donatella; Tabarrini, Oriana; Kaatz, Glenn W; Barreca, Maria L; Sabatini, Stefano; Cecchetti, Violetta

2017-02-23

An intriguing opportunity to address antimicrobial resistance is represented by the inhibition of efflux pumps. Focusing on NorA, the most important efflux pump of Staphylococcus aureus, an efflux pump inhibitors (EPIs) library was used for ligand-based pharmacophore modeling studies. By exploitation of the obtained models, an in silico drug repositioning approach allowed for the identification of novel and potent NorA EPIs.

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

PubMed Central

Choi, Joonhyeok; Lee, You-Mie; Jee, Jun-Goo

2017-01-01

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors. PMID:29283382

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-05-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-04-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications

PubMed Central

Murteira, Susana; Millier, Aurélie; Ghezaiel, Zied; Lamure, Michel

2014-01-01

Background Repurposing has become a mainstream strategy in drug development, but it faces multiple challenges, amongst them the increasing and ever changing regulatory framework. This is the second study of a series of three-part publication project with the ultimate goal of understanding the market access rationale and conditions attributed to drug repurposing in the United States and in Europe. The aim of the current study to evaluate the regulatory path associated with each type of repurposing strategy according to the previously proposed nomenclature in the first article of this series. Methods From the cases identified, a selection process retrieved a total of 141 case studies in all countries, harmonized for data availability and common approval in the United States and in Europe. Regulatory information for each original and repurposed drug product was extracted, and several related regulatory attributes were also extracted such as, designation change and filing before or after patent expiry, among others. Descriptive analyses were conducted to determine trends and to investigate potential associations between the different regulatory paths and attributes of interest, for reformulation and repositioning cases separately. Results Within the studied European countries, most of the applications for reformulated products were filed through national applications. In contrast, for repositioned products, the centralized procedure was the most frequent regulatory pathway. Most of the repurposing cases were approved before patent expiry, and those cases have followed more complex regulatory pathways in the United States and in Europe. For new molecular entities filed in the United States, a similar number of cases were developed by serendipity and by a hypothesis-driven approach. However, for the new indication's regulatory pathway in the United States, most of the cases were developed through a hypothesis-driven approach. Conclusion The regulations in the United States and in Europe for drug repositionings and reformulations allowed confirming that repositioning strategies were usually filed under a more complex regulatory process than reformulations. Also, it seems that parameters such as patent expiry and type of repositioning approach or reformulation affect the regulatory pathways chosen for each case. PMID:27226839

The prince and the pauper. A tale of anticancer targeted agents.

PubMed

Dueñas-González, Alfonso; García-López, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; González-Fierro, Aurora; Candelaria, Myrna

2008-10-23

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.

Drug-target interaction prediction: A Bayesian ranking approach.

PubMed

Peska, Ladislav; Buza, Krisztian; Koller, Júlia

2017-12-01

In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning - finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches. We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account. Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively. Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug-centric repositioning scenarios. BRDTI Software and supplementary materials are available online at www.ksi.mff.cuni.cz/∼peska/BRDTI. Copyright © 2017 Elsevier B.V. All rights reserved.

Computer-aided design and computer-aided manufacturing cutting guides and customized titanium plates are useful in upper maxilla waferless repositioning.

PubMed

Mazzoni, Simona; Bianchi, Alberto; Schiariti, Giulio; Badiali, Giovanni; Marchetti, Claudio

2015-04-01

The purpose of the present study was to develop a computer-aided design (CAD) and computer-aided manufacturing (CAM) technique that enabled fabrication of surgical cutting guides and titanium fixation plates that would allow the upper maxilla to be repositioned correctly without a surgical splint in orthognathic patients. Ten patients were recruited. A complete CAD-CAM workflow for orthognathic surgery has 3 steps: 1) virtual planning of the surgical treatment, 2) CAD-CAM and 3-dimensional printing of customized surgical devices (surgical cutting guide and titanium fixation plates), and 3) computer-aided surgery. Upper maxilla repositioning was performed in a waferless manner using a CAD-CAM device: the surgical cutting guide was used during surgery to pilot the osteotomy line that had been planned preoperatively at the computer and the custom-made fixation titanium plates allowed desired repositioning of the maxilla. To evaluate the reproducibility of this CAD-CAM orthognathic surgical method, the virtually planned and actually achieved positions of the upper maxilla were compared. Overlap errors using a threshold value smaller than 2 mm were evaluated, and the frequency of such errors was used as a measurement of accuracy. By this definition, the accuracy was 100% in 7 patients (range in all patients, 62 to 100%; median, 92.7%). These results tend to confirm that the use of CAD-CAM cutting guides and customized titanium plates for upper maxilla repositioning represents a promising method for the accurate reproduction of preoperative virtual planning without the use of surgical splints. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Larval Zebrafish Model for FDA-Approved Drug Repositioning for Tobacco Dependence Treatment

PubMed Central

Cousin, Margot A.; Ebbert, Jon O.; Wiinamaki, Amanda R.; Urban, Mark D.; Argue, David P.; Ekker, Stephen C.; Klee, Eric W.

2014-01-01

Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA) may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physician-vetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation. PMID:24658307

Advanced systems biology methods in drug discovery and translational biomedicine.

PubMed

Zou, Jun; Zheng, Ming-Wu; Li, Gen; Su, Zhi-Guang

2013-01-01

Systems biology is in an exponential development stage in recent years and has been widely utilized in biomedicine to better understand the molecular basis of human disease and the mechanism of drug action. Here, we discuss the fundamental concept of systems biology and its two computational methods that have been commonly used, that is, network analysis and dynamical modeling. The applications of systems biology in elucidating human disease are highlighted, consisting of human disease networks, treatment response prediction, investigation of disease mechanisms, and disease-associated gene prediction. In addition, important advances in drug discovery, to which systems biology makes significant contributions, are discussed, including drug-target networks, prediction of drug-target interactions, investigation of drug adverse effects, drug repositioning, and drug combination prediction. The systems biology methods and applications covered in this review provide a framework for addressing disease mechanism and approaching drug discovery, which will facilitate the translation of research findings into clinical benefits such as novel biomarkers and promising therapies.

How good are publicly available web services that predict bioactivity profiles for drug repurposing?

PubMed

Murtazalieva, K A; Druzhilovskiy, D S; Goel, R K; Sastry, G N; Poroikov, V V

2017-10-01

Drug repurposing provides a non-laborious and less expensive way for finding new human medicines. Computational assessment of bioactivity profiles shed light on the hidden pharmacological potential of the launched drugs. Currently, several freely available computational tools are available via the Internet, which predict multitarget profiles of drug-like compounds. They are based on chemical similarity assessment (ChemProt, SuperPred, SEA, SwissTargetPrediction and TargetHunter) or machine learning methods (ChemProt and PASS). To compare their performance, this study has created two evaluation sets, consisting of (1) 50 well-known repositioned drugs and (2) 12 drugs recently patented for new indications. In the first set, sensitivity values varied from 0.64 (TarPred) to 1.00 (PASS Online) for the initial indications and from 0.64 (TarPred) to 0.98 (PASS Online) for the repurposed indications. In the second set, sensitivity values varied from 0.08 (SuperPred) to 1.00 (PASS Online) for the initial indications and from 0.00 (SuperPred) to 1.00 (PASS Online) for the repurposed indications. Thus, this analysis demonstrated that the performance of machine learning methods surpassed those of chemical similarity assessments, particularly in the case of novel repurposed indications.

DenguePredict: An Integrated Drug Repositioning Approach towards Drug Discovery for Dengue.

PubMed

Wang, QuanQiu; Xu, Rong

2015-01-01

Dengue is a viral disease of expanding global incidence without cures. Here we present a drug repositioning system (DenguePredict) leveraging upon a unique drug treatment database and vast amounts of disease- and drug-related data. We first constructed a large-scale genetic disease network with enriched dengue genetics data curated from biomedical literature. We applied a network-based ranking algorithm to find dengue-related diseases from the disease network. We then developed a novel algorithm to prioritize FDA-approved drugs from dengue-related diseases to treat dengue. When tested in a de-novo validation setting, DenguePredict found the only two drugs tested in clinical trials for treating dengue and ranked them highly: chloroquine ranked at top 0.96% and ivermectin at top 22.75%. We showed that drugs targeting immune systems and arachidonic acid metabolism-related apoptotic pathways might represent innovative drugs to treat dengue. In summary, DenguePredict, by combining comprehensive disease- and drug-related data and novel algorithms, may greatly facilitate drug discovery for dengue.

Network-based machine learning and graph theory algorithms for precision oncology.

PubMed

Zhang, Wei; Chien, Jeremy; Yong, Jeongsik; Kuang, Rui

2017-01-01

Network-based analytics plays an increasingly important role in precision oncology. Growing evidence in recent studies suggests that cancer can be better understood through mutated or dysregulated pathways or networks rather than individual mutations and that the efficacy of repositioned drugs can be inferred from disease modules in molecular networks. This article reviews network-based machine learning and graph theory algorithms for integrative analysis of personal genomic data and biomedical knowledge bases to identify tumor-specific molecular mechanisms, candidate targets and repositioned drugs for personalized treatment. The review focuses on the algorithmic design and mathematical formulation of these methods to facilitate applications and implementations of network-based analysis in the practice of precision oncology. We review the methods applied in three scenarios to integrate genomic data and network models in different analysis pipelines, and we examine three categories of network-based approaches for repositioning drugs in drug-disease-gene networks. In addition, we perform a comprehensive subnetwork/pathway analysis of mutations in 31 cancer genome projects in the Cancer Genome Atlas and present a detailed case study on ovarian cancer. Finally, we discuss interesting observations, potential pitfalls and future directions in network-based precision oncology.

Computational repositioning of ethno medicine elucidated gB-gH-gL complex as novel anti herpes drug target

PubMed Central

2013-01-01

Background Herpes viruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity. They remain latent in the host cells and can cause recurrent infections that might prove fatal. These viruses are known to infect the host cells by causing the fusion of viral and host cell membrane proteins. Fusion is achieved with the help of conserved fusion machinery components, glycoproteins gB, heterodimer gH-gL complex along with other non-conserved components. Whereas, another important glycoprotein gD without which viral entry to the cell is not possible, acts as a co-activator for the gB-gH-gL complex formation. Thus, this complex formation interface is the most promising drug target for the development of novel anti-herpes drug candidates. In the present study, we propose a model for binding of gH-gL to gB glycoprotein leading from pre to post conformational changes during gB-gH-gL complex formation and reported the key residues involved in this binding activity along with possible binding site locations. To validate the drug targetability of our proposed binding site, we have repositioned some of the most promising in vitro, in vivo validated anti-herpes molecules onto the proposed binding site of gH-gL complex in a computational approach. Methods Hex 6.3 standalone software was used for protein-protein docking studies. Arguslab 4.0.1 and Accelrys® Discovery Studio 3.1 Visualizer softwares were used for semi-flexible docking studies and visualizing the interactions respectively. Protein receptors and ethno compounds were retrieved from Protein Data Bank (PDB) and Pubchem databases respectively. Lipinski’s Filter, Osiris Property Explorer and Lazar online servers were used to check the pharmaceutical fidelity of the drug candidates. Results Through protein-protein docking studies, it was identified that the amino acid residues VAL342, GLU347, SER349, TYR355, SER388, ASN395, HIS398 and ALA387 of gH-gL complex play an active role in its binding activity with gB. Semi flexible docking analysis of the most promising in vitro, in vivo validated anti-herpes molecules targeting the above mentioned key residues of gH-gL complex showed that all the analyzed ethno medicinal compounds have successfully docked into the proposed binding site of gH-gL glycoprotein with binding energy range between -10.4 to -6.4 K.cal./mol. Conclusions Successful repositioning of the analyzed compounds onto the proposed binding site confirms the drug targetability of gH-gL complex. Based on the free binding energy and pharmacological properties, we propose (3-chloro phenyl) methyl-3,4,5 trihydroxybenzoate as worth a small ethno medicinal lead molecule for further development as potent anti-herpes drug candidate targeting gB-gH-gL complex formation interface. PMID:23587166

A network-based drug repositioning infrastructure for precision cancer medicine through targeting significantly mutated genes in the human cancer genomes.

PubMed

Cheng, Feixiong; Zhao, Junfei; Fooksa, Michaela; Zhao, Zhongming

2016-07-01

Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics. We proposed an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network. We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1). In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Network-Based Approaches in Drug Discovery and Early Development

PubMed Central

Harrold, JM; Ramanathan, M; Mager, DE

2015-01-01

Identification of novel targets is a critical first step in the drug discovery and development process. Most diseases such as cancer, metabolic disorders, and neurological disorders are complex, and their pathogenesis involves multiple genetic and environmental factors. Finding a viable drug target–drug combination with high potential for yielding clinical success within the efficacy–toxicity spectrum is extremely challenging. Many examples are now available in which network-based approaches show potential for the identification of novel targets and for the repositioning of established targets. The objective of this article is to highlight network approaches for identifying novel targets with greater chances of gaining approved drugs with maximal efficacy and minimal side effects. Further enhancement of these approaches may emerge from effectively integrating computational systems biology with pharmacodynamic systems analysis. Coupling genomics, proteomics, and metabolomics databases with systems pharmacology modeling may aid in the development of disease-specific networks that can be further used to build confidence in target identification. PMID:24025802

Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding

PubMed Central

Iskar, Murat; Zeller, Georg; Blattmann, Peter; Campillos, Monica; Kuhn, Michael; Kaminska, Katarzyna H; Runz, Heiko; Gavin, Anne-Claude; Pepperkok, Rainer; van Noort, Vera; Bork, Peer

2013-01-01

In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of α-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology. PMID:23632384

Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models

PubMed Central

Bondarenko, Maryna; Laluce, Nahuel Cesatti; Rozados, Viviana; Nicolas, André; Carré, Manon; Scharovsky, O. Graciela; Márquez, Mauricio Menacho

2017-01-01

Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low. Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy. In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models. By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0.001), mitochondrial activity (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). In vivo studies in immunocompetent mice confirmed the potential of this combination in reducing tumor growth (P < 0.001) and preventing metastasis (P < 0.05). Taken together our results suggest that metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control, with no symptoms of toxicity. PMID:27926515

A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors

PubMed Central

Jahchan, Nadine S; Dudley, Joel T; Mazur, Pawel K; Flores, Natasha; Yang, Dian; Palmerton, Alec; Zmoos, Anne-Flore; Vaka, Dedeepya; Tran, Kim QT; Zhou, Margaret; Krasinska, Karolina; Riess, Jonathan W; Neal, Joel W; Khatri, Purvesh; Park, Kwon S; Butte, Atul J; Sage, Julien

2013-01-01

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. PMID:24078773

Big Data Mining and Adverse Event Pattern Analysis in Clinical Drug Trials

PubMed Central

Federer, Callie; Yoo, Minjae

2016-01-01

Abstract Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov (https://clinicaltrials.gov/), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov. Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs. PMID:27631620

Big Data Mining and Adverse Event Pattern Analysis in Clinical Drug Trials.

PubMed

Federer, Callie; Yoo, Minjae; Tan, Aik Choon

2016-12-01

Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov ( https://clinicaltrials.gov/ ), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov . Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs.

Prediction of polypharmacological profiles of drugs by the integration of chemical, side effect, and therapeutic space.

PubMed

Cheng, Feixiong; Li, Weihua; Wu, Zengrui; Wang, Xichuan; Zhang, Chen; Li, Jie; Liu, Guixia; Tang, Yun

2013-04-22

Prediction of polypharmacological profiles of drugs enables us to investigate drug side effects and further find their new indications, i.e. drug repositioning, which could reduce the costs while increase the productivity of drug discovery. Here we describe a new computational framework to predict polypharmacological profiles of drugs by the integration of chemical, side effect, and therapeutic space. On the basis of our previous developed drug side effects database, named MetaADEDB, a drug side effect similarity inference (DSESI) method was developed for drug-target interaction (DTI) prediction on a known DTI network connecting 621 approved drugs and 893 target proteins. The area under the receiver operating characteristic curve was 0.882 ± 0.011 averaged from 100 simulated tests of 10-fold cross-validation for the DSESI method, which is comparative with drug structural similarity inference and drug therapeutic similarity inference methods. Seven new predicted candidate target proteins for seven approved drugs were confirmed by published experiments, with the successful hit rate more than 15.9%. Moreover, network visualization of drug-target interactions and off-target side effect associations provide new mechanism-of-action of three approved antipsychotic drugs in a case study. The results indicated that the proposed methods could be helpful for prediction of polypharmacological profiles of drugs.

Drug-disease association and drug-repositioning predictions in complex diseases using causal inference-probabilistic matrix factorization.

PubMed

Yang, Jihong; Li, Zheng; Fan, Xiaohui; Cheng, Yiyu

2014-09-22

The high incidence of complex diseases has become a worldwide threat to human health. Multiple targets and pathways are perturbed during the pathological process of complex diseases. Systematic investigation of complex relationship between drugs and diseases is necessary for new association discovery and drug repurposing. For this purpose, three causal networks were constructed herein for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. A causal inference-probabilistic matrix factorization (CI-PMF) approach was proposed to predict and classify drug-disease associations, and further used for drug-repositioning predictions. First, multilevel systematic relations between drugs and diseases were integrated from heterogeneous databases to construct causal networks connecting drug-target-pathway-gene-disease. Then, the association scores between drugs and diseases were assessed by evaluating a drug's effects on multiple targets and pathways. Furthermore, PMF models were learned based on known interactions, and associations were then classified into three types by trained models. Finally, therapeutic associations were predicted based upon the ranking of association scores and predicted association types. In terms of drug-disease association prediction, modified causal inference included in CI-PMF outperformed existing causal inference with a higher AUC (area under receiver operating characteristic curve) score and greater precision. Moreover, CI-PMF performed better than single modified causal inference in predicting therapeutic drug-disease associations. In the top 30% of predicted associations, 58.6% (136/232), 50.8% (31/61), and 39.8% (140/352) hit known therapeutic associations, while precisions obtained by the latter were only 10.2% (231/2264), 8.8% (36/411), and 9.7% (189/1948). Clinical verifications were further conducted for the top 100 newly predicted therapeutic associations. As a result, 21, 12, and 32 associations have been studied and many treatment effects of drugs on diseases were investigated for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. Related chains in causal networks were extracted for these 65 clinical-verified associations, and we further illustrated the therapeutic role of etodolac in breast cancer by inferred chains. Overall, CI-PMF is a useful approach for associating drugs with complex diseases and provides potential values for drug repositioning.

Prediction of drug indications based on chemical interactions and chemical similarities.

PubMed

Huang, Guohua; Lu, Yin; Lu, Changhong; Zheng, Mingyue; Cai, Yu-Dong

2015-01-01

Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs.

Prediction of Drug Indications Based on Chemical Interactions and Chemical Similarities

PubMed Central

Huang, Guohua; Lu, Yin; Lu, Changhong; Cai, Yu-Dong

2015-01-01

Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs. PMID:25821813

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

PubMed

Bergquist, Robert; Utzinger, Jürg; Keiser, Jennifer

2017-03-28

The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.

Predicting new drug indications from network analysis

NASA Astrophysics Data System (ADS)

Mohd Ali, Yousoff Effendy; Kwa, Kiam Heong; Ratnavelu, Kurunathan

This work adapts centrality measures commonly used in social network analysis to identify drugs with better positions in drug-side effect network and drug-indication network for the purpose of drug repositioning. Our basic hypothesis is that drugs having similar phenotypic profiles such as side effects may also share similar therapeutic properties based on related mechanism of action and vice versa. The networks were constructed from Side Effect Resource (SIDER) 4.1 which contains 1430 unique drugs with side effects and 1437 unique drugs with indications. Within the giant components of these networks, drugs were ranked based on their centrality scores whereby 18 prominent drugs from the drug-side effect network and 15 prominent drugs from the drug-indication network were identified. Indications and side effects of prominent drugs were deduced from the profiles of their neighbors in the networks and compared to existing clinical studies while an optimum threshold of similarity among drugs was sought for. The threshold can then be utilized for predicting indications and side effects of all drugs. Similarities of drugs were measured by the extent to which they share phenotypic profiles and neighbors. To improve the likelihood of accurate predictions, only profiles such as side effects of common or very common frequencies were considered. In summary, our work is an attempt to offer an alternative approach to drug repositioning using centrality measures commonly used for analyzing social networks.

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

PubMed

Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

2018-02-12

There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

New Therapeutic Uses for Existing Drugs.

PubMed

Austin, Bobbie Ann; Gadhia, Ami D

2017-01-01

Eighty percent of drugs that enter human clinical testing are never approved for use. This means that for every five drugs that make it into the clinic, there are four that failed to show effectiveness for treating the disease or condition the drug was designed to treat.This high failure rate means there are many existing, partially developed therapeutic candidates with known pharmacology, formulation, and potential toxicity. Finding new uses for existing experimental drugs or biologics "repositioning" builds upon previous research and development efforts, so new candidate therapies can be advanced to clinical trials for a new use more quickly than starting from scratch.Federal funding initiatives in the U.S. and UK started to support pre-clinical /or early stage trials for repositioning existing experimental drugs or biologics (therapies). This chapter covers some of the process issues that have been solved and the remaining challenges that are still in need of solutions. The chapter is primarily written from a U.S. federal funding perspective. The general concepts could be applied more globally to benefit rare and neglected disease populations. The drug development and process bottlenecks are the same for both rare and common disease.

Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning

PubMed Central

Langhans, Sigrid A.

2018-01-01

Drug development is a lengthy and costly process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation and clinical trials culminating in approval for clinical use. An important step in this process is high-throughput screening (HTS) of small compound libraries for lead identification. Currently, the majority of cell-based HTS is being carried out on cultured cells propagated in two-dimensions (2D) on plastic surfaces optimized for tissue culture. At the same time, compelling evidence suggests that cells cultured in these non-physiological conditions are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to be a significant contributor to the high failure rate in drug discovery, where only a low percentage of drugs investigated ever make it through the gamut of testing and approval to the market. Thus, three-dimensional (3D) cell culture technologies that more closely resemble in vivo cell environments are now being pursued with intensity as they are expected to accommodate better precision in drug discovery. Here we will review common approaches to 3D culture, discuss the significance of 3D cultures in drug resistance and drug repositioning and address some of the challenges of applying 3D cell cultures to high-throughput drug discovery. PMID:29410625

Neuroblastoma, a Paradigm for Big Data Science in Pediatric Oncology.

PubMed

Salazar, Brittany M; Balczewski, Emily A; Ung, Choong Yong; Zhu, Shizhen

2016-12-27

Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring "big data" applications in pediatric oncology. Computational strategies derived from big data science-network- and machine learning-based modeling and drug repositioning-hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which "big data" and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

Old wines in new bottles: Repurposing opportunities for Parkinson's disease.

PubMed

Kakkar, Ashish Kumar; Singh, Harmanjit; Medhi, Bikash

2018-07-05

Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by accumulation of Lewy bodies and profound loss of substantia nigra dopaminergic neurons. PD symptomatology is now recognized to include both cardinal motor as well as clinically significant non-motor symptoms. Despite intensive research, the current understanding of molecular mechanisms underlying neurodegeneration in PD is limited and has hampered the development of novel symptomatic and disease modifying therapies. The currently available treatment options are only partially or transiently effective and fail to restore the lost dopaminergic neurons or retard disease progression. Given the escalating drug development costs, lengthening timelines and declining R&D efficiency, industry and academia are increasingly focusing on ways to repurpose existing molecules as an accelerated route for drug discovery. The field of PD therapeutics is witnessing vigorous repurposing activity supported by big data analytics, computational models, and high-throughput drug screening systems. Here we review the mechanisms, efficacy, and safety of several emerging drugs currently aspiring to be repositioned for PD pharmacotherapy. Copyright © 2018 Elsevier B.V. All rights reserved.

A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium.

PubMed

Kazakiewicz, Denis; Karr, Jonathan R; Langner, Karol M; Plewczynski, Dariusz

2015-12-01

Bacteria are increasingly resistant to existing antibiotics, which target a narrow range of pathways. New methods are needed to identify targets, including repositioning targets among distantly related species. We developed a novel combination of systems and structural modeling and bioinformatics to reposition known antibiotics and targets to new species. We applied this approach to Mycoplasma genitalium, a common cause of urethritis. First, we used quantitative metabolic modeling to identify enzymes whose expression affects the cellular growth rate. Second, we searched the literature for inhibitors of homologs of the most fragile enzymes. Next, we used sequence alignment to assess that the binding site is shared by M. genitalium, but not by humans. Lastly, we used molecular docking to verify that the reported inhibitors preferentially interact with M. genitalium proteins over their human homologs. Thymidylate kinase was the top predicted target and piperidinylthymines were the top compounds. Further work is needed to experimentally validate piperidinylthymines. In summary, combined systems and structural modeling is a powerful tool for drug repositioning. Copyright © 2015 Elsevier Ltd. All rights reserved.

In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

PubMed Central

Neves, Bruno J.; Braga, Rodolpho C.; Bezerra, José C. B.; Cravo, Pedro V. L.; Andrade, Carolina H.

2015-01-01

Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. PMID:25569258

Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions.

PubMed

Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A

2011-01-01

Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era. Copyright © 2011 Elsevier Ltd. All rights reserved.

Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Y Cho; J Vermeire; J Merkel

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a 'proof-of-concept' for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibitionmore » of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.« less

Data integration to prioritize drugs using genomics and curated data.

PubMed

Louhimo, Riku; Laakso, Marko; Belitskin, Denis; Klefström, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa

2016-01-01

Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.

The Precise Repositioning Instrument for Genioplasty and a Three-Dimensional Printing Technique for Treatment of Complex Facial Asymmetry.

PubMed

Wang, Lin; Tian, Dan; Sun, Xiumei; Xiao, Yanju; Chen, Li; Wu, Guomin

2017-08-01

Facial asymmetry is very common in maxillofacial deformities. It is difficult to achieve accurate reconstruction. With the help of 3D printing models and surgical templates, the osteotomy line and the amount of bone grinding can be accurate. Also, by means of the precise repositioning instrument, the repositioning of genioplasty can be accurate and quick. In this study, we present a three-dimensional printing technique and the precise repositioning instrument to guide the osteotomy and repositioning, and illustrate their feasibility and validity. Eight patients with complex facial asymmetries were studied. A precise 3D printing model was obtained. We made the preoperative design and surgical templates according to it. The surgical templates and precise repositioning instrument were used to obtain an accurate osteotomy and repositioning during the operation. Postoperative measurements were made based on computed tomographic data, including chin point deviation as well as the symmetry of the mandible evaluated by 3D curve functions. All patients obtained satisfactory esthetic results, and no recurrences occurred during follow-up. The results showed that we achieved clinically acceptable precision for the mandible and chin. The mean and SD of ICC between R-Post and L-Post were 0.973 ± 0.007. The mean and SD of chin point deviation 6 months after the operation were 0.63 ± 0.19 mm. The results of this study suggest that the three-dimensional printing technique and the precise repositioning instrument could aid in making better operation designs and more accurate manipulation in orthognathic surgery for complex facial asymmetry. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Reverse screening methods to search for the protein targets of chemopreventive compounds

NASA Astrophysics Data System (ADS)

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-05-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and grasp the types of calculations used in protein target fishing. In addition, we review the main features of these methods, programs and databases and provide a variety of examples illustrating the application of one or a combination of reverse screening methods for accurate target prediction.

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds.

PubMed

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-01-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and grasp the types of calculations used in protein target fishing. In addition, we review the main features of these methods, programs and databases and provide a variety of examples illustrating the application of one or a combination of reverse screening methods for accurate target prediction.

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds

PubMed Central

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-01-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and grasp the types of calculations used in protein target fishing. In addition, we review the main features of these methods, programs and databases and provide a variety of examples illustrating the application of one or a combination of reverse screening methods for accurate target prediction. PMID:29868550

Tools for in silico target fishing.

PubMed

Cereto-Massagué, Adrià; Ojeda, María José; Valls, Cristina; Mulero, Miquel; Pujadas, Gerard; Garcia-Vallve, Santiago

2015-01-01

Computational target fishing methods are designed to identify the most probable target of a query molecule. This process may allow the prediction of the bioactivity of a compound, the identification of the mode of action of known drugs, the detection of drug polypharmacology, drug repositioning or the prediction of the adverse effects of a compound. The large amount of information regarding the bioactivity of thousands of small molecules now allows the development of these types of methods. In recent years, we have witnessed the emergence of many methods for in silico target fishing. Most of these methods are based on the similarity principle, i.e., that similar molecules might bind to the same targets and have similar bioactivities. However, the difficult validation of target fishing methods hinders comparisons of the performance of each method. In this review, we describe the different methods developed for target prediction, the bioactivity databases most frequently used by these methods, and the publicly available programs and servers that enable non-specialist users to obtain these types of predictions. It is expected that target prediction will have a large impact on drug development and on the functional food industry. Copyright © 2014 Elsevier Inc. All rights reserved.

Alzheimer's disease master regulators analysis: search for potential molecular targets and drug repositioning candidates.

PubMed

Vargas, D M; De Bastiani, M A; Zimmer, E R; Klamt, F

2018-06-23

Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets. In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing. We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat). Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.

Repositioning approved drugs for the treatment of problematic cancers using a screening approach

PubMed Central

Kuttler, Fabien; Banfi, Damiano; Turcatti, Gerardo; Dyson, Paul J.

2017-01-01

Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan. PMID:28166232

Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes.

PubMed

Rafehi, Haloom; Kaspi, Antony; Ziemann, Mark; Okabe, Jun; Karagiannis, Tom C; El-Osta, Assam

2017-01-01

Given the skyrocketing costs to develop new drugs, repositioning of approved drugs, such as histone deacetylase (HDAC) inhibitors, may be a promising strategy to develop novel therapies. However, a gap exists in the understanding and advancement of these agents to meaningful translation for which new indications may emerge. To address this, we performed systems-level analyses of 33 independent HDAC inhibitor microarray studies. Based on network analysis, we identified enrichment for pathways implicated in metabolic syndrome and diabetes (insulin receptor signaling, lipid metabolism, immunity and trafficking). Integration with ENCODE ChIP-seq datasets identified suppression of EP300 target genes implicated in diabetes. Experimental validation indicates reversal of diabetes-associated EP300 target genes in primary vascular endothelial cells derived from a diabetic individual following inhibition of HDACs (by SAHA), EP300, or EP300 knockdown. Our computational systems biology approach provides an adaptable framework for the prediction of novel therapeutics for existing disease.

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; King, Benjamin L.; Wiegers, Jolene; Grondin, Cynthia J.; Sciaky, Daniela; Johnson, Robin J.; Mattingly, Carolyn J.

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD’s gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects. PMID:27171405

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; King, Benjamin L; Wiegers, Jolene; Grondin, Cynthia J; Sciaky, Daniela; Johnson, Robin J; Mattingly, Carolyn J

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

Assembly and positioning of actomyosin rings by contractility and planar cell polarity

PubMed Central

Sehring, Ivonne M; Recho, Pierre; Denker, Elsa; Kourakis, Matthew; Mathiesen, Birthe; Hannezo, Edouard; Dong, Bo; Jiang, Di

2015-01-01

The actomyosin cytoskeleton is a primary force-generating mechanism in morphogenesis, thus a robust spatial control of cytoskeletal positioning is essential. In this report, we demonstrate that actomyosin contractility and planar cell polarity (PCP) interact in post-mitotic Ciona notochord cells to self-assemble and reposition actomyosin rings, which play an essential role for cell elongation. Intriguingly, rings always form at the cells′ anterior edge before migrating towards the center as contractility increases, reflecting a novel dynamical property of the cortex. Our drug and genetic manipulations uncover a tug-of-war between contractility, which localizes cortical flows toward the equator and PCP, which tries to reposition them. We develop a simple model of the physical forces underlying this tug-of-war, which quantitatively reproduces our results. We thus propose a quantitative framework for dissecting the relative contribution of contractility and PCP to the self-assembly and repositioning of cytoskeletal structures, which should be applicable to other morphogenetic events. DOI: http://dx.doi.org/10.7554/eLife.09206.001 PMID:26486861

In Silico target fishing: addressing a "Big Data" problem by ligand-based similarity rankings with data fusion.

PubMed

Liu, Xian; Xu, Yuan; Li, Shanshan; Wang, Yulan; Peng, Jianlong; Luo, Cheng; Luo, Xiaomin; Zheng, Mingyue; Chen, Kaixian; Jiang, Hualiang

2014-01-01

Ligand-based in silico target fishing can be used to identify the potential interacting target of bioactive ligands, which is useful for understanding the polypharmacology and safety profile of existing drugs. The underlying principle of the approach is that known bioactive ligands can be used as reference to predict the targets for a new compound. We tested a pipeline enabling large-scale target fishing and drug repositioning, based on simple fingerprint similarity rankings with data fusion. A large library containing 533 drug relevant targets with 179,807 active ligands was compiled, where each target was defined by its ligand set. For a given query molecule, its target profile is generated by similarity searching against the ligand sets assigned to each target, for which individual searches utilizing multiple reference structures are then fused into a single ranking list representing the potential target interaction profile of the query compound. The proposed approach was validated by 10-fold cross validation and two external tests using data from DrugBank and Therapeutic Target Database (TTD). The use of the approach was further demonstrated with some examples concerning the drug repositioning and drug side-effects prediction. The promising results suggest that the proposed method is useful for not only finding promiscuous drugs for their new usages, but also predicting some important toxic liabilities. With the rapid increasing volume and diversity of data concerning drug related targets and their ligands, the simple ligand-based target fishing approach would play an important role in assisting future drug design and discovery.

A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses.

PubMed

Bhakat, Soumendranath; Karubiu, Wilson; Jayaprakash, Venkatesan; Soliman, Mahmoud E S

2014-11-24

Neglected tropical diseases are major causes of fatality in poverty stricken regions across Africa, Asia and some part of America. The combined potential health risk associated with arthropod-borne viruses (arboviruses); Dengue virus (DENV), West Nile Virus (WNV) and Chikungunya Virus (CHIKV) is immense. These arboviruses are either emerging or re-emerging in many regions with recent documented outbreaks in the United States. Despite several recent evidences of emergence, currently there are no approved drugs or vaccines available to counter these diseases. Non-structural proteins encoded by these RNA viruses are essential for their replication and maturation and thus may offer ideal targets for developing antiviral drugs. In recent years, several protease inhibitors have been sourced from plant extract, synthesis, computer aided drug design and high throughput screening as well as through drug reposition based approaches to target the non-structural proteins. The protease inhibitors have shown different levels of inhibition and may thus provide template to develop selective and potent drugs against these devastating arboviruses. This review seeks to shed light on the design and development of antiviral drugs against DENV, WNV and CHIKV to date. To the best of our knowledge, this review provides the first comprehensive update on the development of protease inhibitors targeting non-structural proteins of three most devastating arboviruses, DENV, WNV and CHIKV. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

PubMed Central

Lohinai, Zoltan; Dome, Peter; Szilagyi, Zsuzsa; Ostoros, Gyula; Moldvay, Judit; Hegedus, Balazs

2016-01-01

Backgrounds Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit. Methods Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified. Results There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828–2.525; p <0.001). Conclusions Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies. PMID:26735301

Combining automatic table classification and relationship extraction in extracting anticancer drug-side effect pairs from full-text articles.

PubMed

Xu, Rong; Wang, QuanQiu

2015-02-01

Anticancer drug-associated side effect knowledge often exists in multiple heterogeneous and complementary data sources. A comprehensive anticancer drug-side effect (drug-SE) relationship knowledge base is important for computation-based drug target discovery, drug toxicity predication and drug repositioning. In this study, we present a two-step approach by combining table classification and relationship extraction to extract drug-SE pairs from a large number of high-profile oncological full-text articles. The data consists of 31,255 tables downloaded from the Journal of Oncology (JCO). We first trained a statistical classifier to classify tables into SE-related and -unrelated categories. We then extracted drug-SE pairs from SE-related tables. We compared drug side effect knowledge extracted from JCO tables to that derived from FDA drug labels. Finally, we systematically analyzed relationships between anti-cancer drug-associated side effects and drug-associated gene targets, metabolism genes, and disease indications. The statistical table classifier is effective in classifying tables into SE-related and -unrelated (precision: 0.711; recall: 0.941; F1: 0.810). We extracted a total of 26,918 drug-SE pairs from SE-related tables with a precision of 0.605, a recall of 0.460, and a F1 of 0.520. Drug-SE pairs extracted from JCO tables is largely complementary to those derived from FDA drug labels; as many as 84.7% of the pairs extracted from JCO tables have not been included a side effect database constructed from FDA drug labels. Side effects associated with anticancer drugs positively correlate with drug target genes, drug metabolism genes, and disease indications. Copyright © 2014 Elsevier Inc. All rights reserved.

Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts

PubMed Central

Kobashigawa, Tsuyoshi

2016-01-01

Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis. PMID:27965978

Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts.

PubMed

Nanke, Yuki; Kobashigawa, Tsuyoshi; Yago, Toru; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2016-01-01

Objectives . Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results . Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions . The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.

Repositioning of proton pump inhibitors in cancer therapy.

PubMed

Lu, Zhen-Ning; Tian, Bing; Guo, Xiu-Li

2017-11-01

Drug repositioning, as a smart way to exploit new molecular targets of a known drug, has been gaining increasing attention in the discovery of anti-cancer drugs. Proton pump inhibitors (PPIs) as benzimidazole derivatives, which are essentially H + -K + -ATPases inhibitors, are commonly used in the treatment of acid-related diseases such as gastric ulcer. In recent years, exploring the new application of PPIs in anti-cancer field has become a hot research topic. Interestingly, cancer cells display an alkaline intracellular pH and an acidic extracellular pH. The extracellular acidity of tumors can be corrected by PPIs that are selectively activated in an acid milieu. It is generally believed that PPIs might provoke disruption of pH homeostasis by targeting V-ATPase on cancer cells, which is the theoretical basis for PPIs to play an anti-cancer role. Numerous studies have shown specialized effects of the PPIs on tumor cell growth, metastasis, chemoresistance, and autophagy. PPIs may really represent new anti-cancer drugs due to better safety and tolerance, the potential selectivity in targeting tumor acidity, and the ability to inhibit mechanism pivotal for cancer homeostasis. In this review, we focus on the new therapeutic applications of PPIs in multiple cancers, explaining the rationale behind this approach and providing practical evidence.

Human Disease-Drug Network Based on Genomic Expression Profiles

PubMed Central

Hu, Guanghui; Agarwal, Pankaj

2009-01-01

Background Drug repositioning offers the possibility of faster development times and reduced risks in drug discovery. With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes. Methodology/Principal Findings We performed a systematic, large-scale analysis of genomic expression profiles of human diseases and drugs to create a disease-drug network. A network of 170,027 significant interactions was extracted from the ∼24.5 million comparisons between ∼7,000 publicly available transcriptomic profiles. The network includes 645 disease-disease, 5,008 disease-drug, and 164,374 drug-drug relationships. At least 60% of the disease-disease pairs were in the same disease area as determined by the Medical Subject Headings (MeSH) disease classification tree. The remaining can drive a molecular level nosology by discovering relationships between seemingly unrelated diseases, such as a connection between bipolar disorder and hereditary spastic paraplegia, and a connection between actinic keratosis and cancer. Among the 5,008 disease-drug links, connections with negative scores suggest new indications for existing drugs, such as the use of some antimalaria drugs for Crohn's disease, and a variety of existing drugs for Huntington's disease; while the positive scoring connections can aid in drug side effect identification, such as tamoxifen's undesired carcinogenic property. From the ∼37K drug-drug relationships, we discover relationships that aid in target and pathway deconvolution, such as 1) KCNMA1 as a potential molecular target of lobeline, and 2) both apoptotic DNA fragmentation and G2/M DNA damage checkpoint regulation as potential pathway targets of daunorubicin. Conclusions/Significance We have automatically generated thousands of disease and drug expression profiles using GEO datasets, and constructed a large scale disease-drug network for effective and efficient drug repositioning as well as drug target/pathway identification. PMID:19657382

Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

PubMed

Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

2015-07-15

Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html. Copyright © 2015 Elsevier Inc. All rights reserved.

Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Kejian, E-mail: kejian.wang.bio@gmail.com; Weng, Zuquan; Sun, Liya

Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. Inmore » the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.« less

Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

PubMed

Yoshida, Go J

2017-03-09

The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

Three-dimensional surgical simulation.

PubMed

Cevidanes, Lucia H C; Tucker, Scott; Styner, Martin; Kim, Hyungmin; Chapuis, Jonas; Reyes, Mauricio; Proffit, William; Turvey, Timothy; Jaskolka, Michael

2010-09-01

In this article, we discuss the development of methods for computer-aided jaw surgery, which allows us to incorporate the high level of precision necessary for transferring virtual plans into the operating room. We also present a complete computer-aided surgery system developed in close collaboration with surgeons. Surgery planning and simulation include construction of 3-dimensional surface models from cone-beam computed tomography, dynamic cephalometry, semiautomatic mirroring, interactive cutting of bone, and bony segment repositioning. A virtual setup can be used to manufacture positioning splints for intraoperative guidance. The system provides further intraoperative assistance with a computer display showing jaw positions and 3-dimensional positioning guides updated in real time during the surgical procedure. The computer-aided surgery system aids in dealing with complex cases with benefits for the patient, with surgical practice, and for orthodontic finishing. Advanced software tools for diagnosis and treatment planning allow preparation of detailed operative plans, osteotomy repositioning, bone reconstructions, surgical resident training, and assessing the difficulties of the surgical procedures before the surgery. Computer-aided surgery can make the elaboration of the surgical plan a more flexible process, increase the level of detail and accuracy of the plan, yield higher operative precision and control, and enhance documentation of cases. 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Computer-Aided Identification of Anticonvulsant Effect of Natural Nonnutritive Sweeteners Stevioside and Rebaudioside A

PubMed Central

Di Ianni, Mauricio E.; del Valle, Mara E.; Enrique, Andrea V.; Rosella, Mara A.; Bruno, Fiorella; Bruno-Blanch, Luis E.

2015-01-01

Abstract Steviol glycosides are natural constituents of Stevia rebaudiana (Bert.) Bert. (Asteraceae) that have recently gained worldwide approval as nonnutritive sweeteners by the Joint Food and Agriculture Organization/World Organization Expert Committee on Food Additives. Cheminformatic tools suggested that the aglycone steviol and several of its phase I metabolites were predicted as potential anticonvulsant agents effective in the seizure animal model maximal electroshock seizure (MES) test. Thus, aqueous infusion from S. rebaudiana was tested in the MES test (mice, intraperitoneal administration), confirming dose-dependent anticonvulsant effect. Afterward, isolated stevioside and rebaudioside A were tested in the MES test, with positive results. Though drug repositioning most often focuses on known therapeutics, this article illustrates the possibilities of this strategy to find new functionalities and therapeutic indications for food constituents and natural products. PMID:26258457

Automatic repositioning of jaw segments for three-dimensional virtual treatment planning of orthognathic surgery.

PubMed

Santos, Rodrigo Mologni Gonçalves Dos; De Martino, José Mario; Passeri, Luis Augusto; Attux, Romis Ribeiro de Faissol; Haiter Neto, Francisco

2017-09-01

To develop a computer-based method for automating the repositioning of jaw segments in the skull during three-dimensional virtual treatment planning of orthognathic surgery. The method speeds up the planning phase of the orthognathic procedure, releasing surgeons from laborious and time-consuming tasks. The method finds the optimal positions for the maxilla, mandibular body, and bony chin in the skull. Minimization of cephalometric differences between measured and standard values is considered. Cone-beam computed tomographic images acquired from four preoperative patients with skeletal malocclusion were used for evaluating the method. Dentofacial problems of the four patients were rectified, including skeletal malocclusion, facial asymmetry, and jaw discrepancies. The results show that the method is potentially able to be used in routine clinical practice as support for treatment-planning decisions in orthognathic surgery. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

PubMed Central

Matthews, Holly; Deakin, Jon; Rajab, May; Idris-Usman, Maryam

2017-01-01

The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product. PMID:28257497

Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer

PubMed Central

Shigemizu, Daichi; Hu, Zhenjun; Hung, Jui-Hung; Huang, Chia-Ling; Wang, Yajie; DeLisi, Charles

2012-01-01

The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine. PMID:22346740

Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer.

PubMed

Senkowski, Wojciech; Zhang, Xiaonan; Olofsson, Maria Hägg; Isacson, Ruben; Höglund, Urban; Gustafsson, Mats; Nygren, Peter; Linder, Stig; Larsson, Rolf; Fryknäs, Mårten

2015-06-01

Because dormant cancer cells in hypoxic and nutrient-deprived regions of solid tumors provide a major obstacle to treatment, compounds targeting those cells might have clinical benefits. Here, we describe a high-throughput drug screening approach, using glucose-deprived multicellular tumor spheroids (MCTS) with inner hypoxia, to identify compounds that specifically target this cell population. We used a concept of drug repositioning-using known molecules for new indications. This is a promising strategy to identify molecules for rapid clinical advancement. By screening 1,600 compounds with documented clinical history, we aimed to identify candidates with unforeseen potential for repositioning as anticancer drugs. Our screen identified five molecules with pronounced MCTS-selective activity: nitazoxanide, niclosamide, closantel, pyrvinium pamoate, and salinomycin. Herein, we show that all five compounds inhibit mitochondrial respiration. This suggests that cancer cells in low glucose concentrations depend on oxidative phosphorylation rather than solely glycolysis. Importantly, continuous exposure to the compounds was required to achieve effective treatment. Nitazoxanide, an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide combined with the cytotoxic drug irinotecan showed anticancer activity in vivo. We here report that the FDA-approved anthelmintic drug nitazoxanide could be a potential candidate for advancement into cancer clinical trials. ©2015 American Association for Cancer Research.

How reliable are ligand-centric methods for Target Fishing?

NASA Astrophysics Data System (ADS)

Peon, Antonio; Dang, Cuong; Ballester, Pedro

2016-04-01

Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict.

Counterclockwise maxillomandibular advancement surgery and disc repositioning: can condylar remodeling in the long-term follow-up be predicted?

PubMed

Gomes, L R; Cevidanes, L H; Gomes, M R; Ruellas, A C; Ryan, D P; Paniagua, B; Wolford, L M; Gonçalves, J R

2017-12-01

This study investigated predictive risk factors of condylar remodeling changes after counterclockwise maxillomandibular advancement (CCW-MMA) and disc repositioning surgery. Forty-one female patients (75 condyles) treated with CCW-MMA and disc repositioning had cone beam computed tomography (CBCT) scans taken pre-surgery, immediately after surgery, and at an average 16 months post-surgery. Pre- and post-surgical three-dimensional models were superimposed using automated voxel-based registration on the cranial base to evaluate condylar displacements after surgery. Regional registration was performed to assess condylar remodeling in the follow-up period. Three-dimensional cephalometrics, shape correspondence (SPHARM-PDM), and volume measurements were applied to quantify changes. Pearson product-moment correlations and multiple regression analysis were performed. Highly statistically significant correlation showed that older patients were more susceptible to overall condylar volume reduction following CCW-MMA and disc repositioning (P≤0.001). Weak but statistically significant correlations were observed between condylar remodeling changes in the follow-up period and pre-surgical facial characteristics, magnitude of the surgical procedure, and condylar displacement changes. After CCW-MMA and disc repositioning, the condyles moved mostly downwards and medially, and were rotated medially and counterclockwise; displacements in the opposite direction were correlated with a greater risk of condylar resorption. Moreover, positional changes with surgery were only weakly associated with remodeling in the follow-up period, suggesting that other risk factors may play a role in condylar resorption. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Analysis of A Drug Target-based Classification System using Molecular Descriptors.

PubMed

Lu, Jing; Zhang, Pin; Bi, Yi; Luo, Xiaomin

2016-01-01

Drug-target interaction is an important topic in drug discovery and drug repositioning. KEGG database offers a drug annotation and classification using a target-based classification system. In this study, we gave an investigation on five target-based classes: (I) G protein-coupled receptors; (II) Nuclear receptors; (III) Ion channels; (IV) Enzymes; (V) Pathogens, using molecular descriptors to represent each drug compound. Two popular feature selection methods, maximum relevance minimum redundancy and incremental feature selection, were adopted to extract the important descriptors. Meanwhile, an optimal prediction model based on nearest neighbor algorithm was constructed, which got the best result in identifying drug target-based classes. Finally, some key descriptors were discussed to uncover their important roles in the identification of drug-target classes.

Drug repurposing in pharmaceutical industry and its impact on market access: market access implications.

PubMed

Murteira, Susana; Millier, Aurélie; Toumi, Mondher

2014-01-01

Drug repurposing is a group of development strategies employed in order to overcome some of the hurdles innate to drug research and development. Drug repurposing includes drug repositioning, reformulation and combination. This study aimed to identify the determinants of successful market access outcome for drug repurposing in the United States of America (USA) and in Europe. The case studies of repurposing strategies were identified through a systematic review of the literature. Price information and reimbursement conditions for all the case studies were collected mainly through access of public datasources. A list of attributes that could be associated with market access outcome (price level and reimbursement conditions) was developed, discussed, and validated by an external expert group. Detailed information for all attributes was researched and collected for each case study. Bivariate regression models were conducted to identify factors associated with price change for all repurposing cases. A similar analysis was performed for reformulation and repositioning cases, in the USA and in Europe, separately. A significance level of 5% was used for all analyses. A total of 144 repurposing case studies were included in the statistical analysis for evaluation of mean price change. Combination cases (the combination of two or more individual drug components) were excluded from the statistical analysis due to the low number of cases retrieved. The main attributes associated with a significant price increase for overall repurposing cases were 'change in administration setting to hospital' (374%, p<0.0001), 'addressing unmet needs' (69%, p<0.05), 'reformulations belonging to Group 3'-that is, change in administration route (117%, p<0.001), and being a repurposed product with the 'same brand name' as the original product (65%, p<0.05). We found that the ability of the repurposed product to address unmet needs, a reformulation where the target product had a different administration route than the source product, and having a similar brand name for repurposed and original products, were variables that impacted a positive price change for repurposed drugs overall. Our research results also suggested that orphan designation could have a positive impact for repositioning in the USA, in particular. Although a change of administration from ambulatory to hospital setting seemed to be significantly correlated with a price increase for the target product, only one case was retrieved for this parameter; as such, it was not possible to infer a firm correlation between this parameter and a change in price.

Drug repurposing in pharmaceutical industry and its impact on market access: market access implications

PubMed Central

Murteira, Susana; Millier, Aurélie; Toumi, Mondher

2014-01-01

Background Drug repurposing is a group of development strategies employed in order to overcome some of the hurdles innate to drug research and development. Drug repurposing includes drug repositioning, reformulation and combination. Objective This study aimed to identify the determinants of successful market access outcome for drug repurposing in the United States of America (USA) and in Europe. Methods The case studies of repurposing strategies were identified through a systematic review of the literature. Price information and reimbursement conditions for all the case studies were collected mainly through access of public datasources. A list of attributes that could be associated with market access outcome (price level and reimbursement conditions) was developed, discussed, and validated by an external expert group. Detailed information for all attributes was researched and collected for each case study. Bivariate regression models were conducted to identify factors associated with price change for all repurposing cases. A similar analysis was performed for reformulation and repositioning cases, in the USA and in Europe, separately. A significance level of 5% was used for all analyses. Results A total of 144 repurposing case studies were included in the statistical analysis for evaluation of mean price change. Combination cases (the combination of two or more individual drug components) were excluded from the statistical analysis due to the low number of cases retrieved. The main attributes associated with a significant price increase for overall repurposing cases were ‘change in administration setting to hospital’ (374%, p<0.0001), ‘addressing unmet needs’ (69%, p<0.05), ‘reformulations belonging to Group 3’—that is, change in administration route (117%, p<0.001), and being a repurposed product with the ‘same brand name’ as the original product (65%, p<0.05). Conclusion We found that the ability of the repurposed product to address unmet needs, a reformulation where the target product had a different administration route than the source product, and having a similar brand name for repurposed and original products, were variables that impacted a positive price change for repurposed drugs overall. Our research results also suggested that orphan designation could have a positive impact for repositioning in the USA, in particular. Although a change of administration from ambulatory to hospital setting seemed to be significantly correlated with a price increase for the target product, only one case was retrieved for this parameter; as such, it was not possible to infer a firm correlation between this parameter and a change in price. PMID:27226833

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the genemore » expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.« less

A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes.

PubMed

Chen, Lei; Lu, Jing; Zhang, Ning; Huang, Tao; Cai, Yu-Dong

2014-04-01

In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC-classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs.

Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor cells.

PubMed

Bonvicini, Francesca; Bua, Gloria; Conti, Ilaria; Manaresi, Elisabetta; Gallinella, Giorgio

2017-07-15

Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis and severe complications mainly in subjects with underlying hematological disorders or with immune system deficits. Currently, there are no specific antiviral drugs for B19V treatment, but identification of compounds inhibiting B19V replication can be pursued by a drug repositioning strategy. In this frame, the present study investigates the activity of hydroxyurea (HU), the only disease-modifying therapy approved for sickle cell disease (SCD), towards B19V replication in the two relevant cellular systems, the UT7/EpoS1 cell line and EPCs. Results demonstrate that HU inhibits B19V replication with EC 50 values of 96.2µM and 147.1µM in UT7/EpoS1 and EPCs, respectively, providing experimental evidence of the antiviral activity of HU towards B19V replication, and confirming the efficacy of a drug discovery process by drug repositioning strategy. The antiviral activity occurs in vitro at concentrations lower than those affecting cellular DNA replication and viability, and at levels measured in plasma samples of SCD patients undergoing HU therapy. HU might determine a dual beneficial effect on SCD patients, not only for the treatment of the disease but also towards a virus responsible for severe complications. Copyright © 2017 Elsevier Inc. All rights reserved.

The human disease network in terms of dysfunctional regulatory mechanisms.

PubMed

Yang, Jing; Wu, Su-Juan; Dai, Wen-Tao; Li, Yi-Xue; Li, Yuan-Yuan

2015-10-08

Elucidation of human disease similarities has emerged as an active research area, which is highly relevant to etiology, disease classification, and drug repositioning. In pioneer studies, disease similarity was commonly estimated according to clinical manifestation. Subsequently, scientists started to investigate disease similarity based on gene-phenotype knowledge, which were inevitably biased to well-studied diseases. In recent years, estimating disease similarity according to transcriptomic behavior significantly enhances the probability of finding novel disease relationships, while the currently available studies usually mine expression data through differential expression analysis that has been considered to have little chance of unraveling dysfunctional regulatory relationships, the causal pathogenesis of diseases. We developed a computational approach to measure human disease similarity based on expression data. Differential coexpression analysis, instead of differential expression analysis, was employed to calculate differential coexpression level of every gene for each disease, which was then summarized to the pathway level. Disease similarity was eventually calculated as the partial correlation coefficients of pathways' differential coexpression values between any two diseases. The significance of disease relationships were evaluated by permutation test. Based on mRNA expression data and a differential coexpression analysis based method, we built a human disease network involving 1326 significant Disease-Disease links among 108 diseases. Compared with disease relationships captured by differential expression analysis based method, our disease links shared known disease genes and drugs more significantly. Some novel disease relationships were discovered, for example, Obesity and cancer, Obesity and Psoriasis, lung adenocarcinoma and S. pneumonia, which had been commonly regarded as unrelated to each other, but recently found to share similar molecular mechanisms. Additionally, it was found that both the type of disease and the type of affected tissue influenced the degree of disease similarity. A sub-network including Allergic asthma, Type 2 diabetes and Chronic kidney disease was extracted to demonstrate the exploration of their common pathogenesis. The present study produces a global view of human diseasome for the first time from the viewpoint of regulation mechanisms, which therefore could provide insightful clues to etiology and pathogenesis, and help to perform drug repositioning and design novel therapeutic interventions.

Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions

PubMed Central

Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A.

2013-01-01

Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin (“old drugs”) to their recently recognized CSC targets (“new uses”) within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the “old drugs–new uses” repurposing strategy to open a new CSC-targeted chemoprevention era. PMID:21600837

A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions

PubMed Central

Iorio, Francesco; Shrestha, Roshan L.; Levin, Nicolas; Boilot, Viviane; Garnett, Mathew J.; Saez-Rodriguez, Julio; Draviam, Viji M.

2015-01-01

We present a novel strategy to identify drug-repositioning opportunities. The starting point of our method is the generation of a signature summarising the consensual transcriptional response of multiple human cell lines to a compound of interest (namely the seed compound). This signature can be derived from data in existing databases, such as the connectivity-map, and it is used at first instance to query a network interlinking all the connectivity-map compounds, based on the similarity of their transcriptional responses. This provides a drug neighbourhood, composed of compounds predicted to share some effects with the seed one. The original signature is then refined by systematically reducing its overlap with the transcriptional responses induced by drugs in this neighbourhood that are known to share a secondary effect with the seed compound. Finally, the drug network is queried again with the resulting refined signatures and the whole process is carried on for a number of iterations. Drugs in the final refined neighbourhood are then predicted to exert the principal mode of action of the seed compound. We illustrate our approach using paclitaxel (a microtubule stabilising agent) as seed compound. Our method predicts that glipizide and splitomicin perturb microtubule function in human cells: a result that could not be obtained through standard signature matching methods. In agreement, we find that glipizide and splitomicin reduce interphase microtubule growth rates and transiently increase the percentage of mitotic cells–consistent with our prediction. Finally, we validated the refined signatures of paclitaxel response by mining a large drug screening dataset, showing that human cancer cell lines whose basal transcriptional profile is anti-correlated to them are significantly more sensitive to paclitaxel and docetaxel. PMID:26452147

Accuracy of three-dimensional facial soft tissue simulation in post-traumatic zygoma reconstruction.

PubMed

Li, P; Zhou, Z W; Ren, J Y; Zhang, Y; Tian, W D; Tang, W

2016-12-01

The aim of this study was to evaluate the accuracy of novel software-CMF-preCADS-for the prediction of soft tissue changes following repositioning surgery for zygomatic fractures. Twenty patients who had sustained an isolated zygomatic fracture accompanied by facial deformity and who were treated with repositioning surgery participated in this study. Cone beam computed tomography (CBCT) scans and three-dimensional (3D) stereophotographs were acquired preoperatively and postoperatively. The 3D skeletal model from the preoperative CBCT data was matched with the postoperative one, and the fractured zygomatic fragments were segmented and aligned to the postoperative position for prediction. Then, the predicted model was matched with the postoperative 3D stereophotograph for quantification of the simulation error. The mean absolute error in the zygomatic soft tissue region between the predicted model and the real one was 1.42±1.56mm for all cases. The accuracy of the prediction (mean absolute error ≤2mm) was 87%. In the subjective assessment it was found that the majority of evaluators considered the predicted model and the postoperative model to be 'very similar'. CMF-preCADS software can provide a realistic, accurate prediction of the facial soft tissue appearance after repositioning surgery for zygomatic fractures. The reliability of this software for other types of repositioning surgery for maxillofacial fractures should be validated in the future. Copyright © 2016. Published by Elsevier Ltd.

Validation of spinal motion with the spine reposition sense device

PubMed Central

Petersen, Cheryl M; Rundquist, Peter J

2009-01-01

Background A sagittal plane spine reposition sense device (SRSD) has been developed. Two questions were addressed with this study concerning the new SRSD: 1) whether spine movement was occurring with the methodology, and 2) where movement was taking place. Methods Sixty-five subjects performed seven trials of repositioning to a two-thirds full flexion position in sitting with X and Y displacement measurements taken at the T4 and L3 levels. The thoracolumbar angle between the T4 and the L3 level was computed and compared between the positions tested. A two (vertebral level of thoracic and lumbar) by seven (trials) mixed model repeated measures ANOVA indicated whether significant differences were present between the thoracic (T4) and lumbar (L3) angular measurements. Results Calculated thoracolumbar angles between T4 and L3 were significantly different for all positions tested indicating spinal movement was occurring with testing. No interactions were found between the seven trials and the two vertebral levels. No significant findings were found between the seven trials but significant differences were found between the two vertebral levels. Conclusion This study indicated spine motion was taking place with the SRSD methodology and movement was found specific to the lumbar spine. These findings support utilizing the SRSD to evaluate changes in spine reposition sense during future intervention studies dealing with low back pain. PMID:19386126

Photogrammetric accuracy measurements of head holder systems used for fractionated radiotherapy.

PubMed

Menke, M; Hirschfeld, F; Mack, T; Pastyr, O; Sturm, V; Schlegel, W

1994-07-30

We describe how stereo photogrammetry can be used to determine immobilization and repositioning accuracies of head holder systems used for fractionated radiotherapy of intracranial lesions. The apparatus consists of two video cameras controlled by a personal computer and a bite block based landmark system. Position and spatial orientation of the landmarks are monitored by the cameras and processed for the real-time calculation of a target point's actual position relative to its initializing position. The target's position is assumed to be invariant with respect to the landmark system. We performed two series of 30 correlated head motion measurements on two test persons. One of the series was done with a thermoplastic device, the other one with a cast device developed for stereotactic treatment at the German Cancer Research Center. Immobilization and repositioning accuracies were determined with respect to a target point situated near the base of the skull. The repositioning accuracies were described in terms of the distributions of the mean displacements of the single motion measurements. Movements of the target in the order of 0.05 mm caused by breathing could be detected with a maximum resolution in time of 12 ms. The data derived from the investigation of the two test persons indicated similar immobilization accuracies for the two devices, but the repositioning errors were larger for the thermoplastic device than for the cast device. Apart from this, we found that for the thermoplastic mask the lateral repositioning error depended on the order in which the mask was closed. The photogrammetric apparatus is a versatile tool for accuracy measurements of head holder devices used for fractionated radiotherapy.

Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance

PubMed Central

Wang, Yi-Jun; Zhang, Yun-Kai; Kathawala, Rishil J.; Chen, Zhe-Sheng

2014-01-01

The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance. PMID:25268163

Scaffold Repurposing of Old Drugs Towards New Cancer Drug Discovery.

PubMed

Chen, Haijun; Wu, Jianlei; Gao, Yu; Chen, Haiying; Zhou, Jia

2016-01-01

As commented by the Nobelist James Black that "The most fruitful basis of the discovery of a new drug is to start with an old drug", drug repurposing represents an attractive drug discovery strategy. Despite the success of several repurposed drugs on the market, the ultimate therapeutic potential of a large number of non-cancer drugs is hindered during their repositioning due to various issues including the limited efficacy and intellectual property. With the increasing knowledge about the pharmacological properties and newly identified targets, the scaffolds of the old drugs emerge as a great treasure-trove towards new cancer drug discovery. In this review, we summarize the recent advances in the development of novel small molecules for cancer therapy by scaffold repurposing with highlighted examples. The relevant strategies, advantages, challenges and future research directions associated with this approach are also discussed.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

3D Surgical Simulation

PubMed Central

Cevidanes, Lucia; Tucker, Scott; Styner, Martin; Kim, Hyungmin; Chapuis, Jonas; Reyes, Mauricio; Proffit, William; Turvey, Timothy; Jaskolka, Michael

2009-01-01

This paper discusses the development of methods for computer-aided jaw surgery. Computer-aided jaw surgery allows us to incorporate the high level of precision necessary for transferring virtual plans into the operating room. We also present a complete computer-aided surgery (CAS) system developed in close collaboration with surgeons. Surgery planning and simulation include construction of 3D surface models from Cone-beam CT (CBCT), dynamic cephalometry, semi-automatic mirroring, interactive cutting of bone and bony segment repositioning. A virtual setup can be used to manufacture positioning splints for intra-operative guidance. The system provides further intra-operative assistance with the help of a computer display showing jaw positions and 3D positioning guides updated in real-time during the surgical procedure. The CAS system aids in dealing with complex cases with benefits for the patient, with surgical practice, and for orthodontic finishing. Advanced software tools for diagnosis and treatment planning allow preparation of detailed operative plans, osteotomy repositioning, bone reconstructions, surgical resident training and assessing the difficulties of the surgical procedures prior to the surgery. CAS has the potential to make the elaboration of the surgical plan a more flexible process, increase the level of detail and accuracy of the plan, yield higher operative precision and control, and enhance documentation of cases. Supported by NIDCR DE017727, and DE018962 PMID:20816308

Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

Effects of Dual Monitor Computer Work Versus Laptop Work on Cervical Muscular and Proprioceptive Characteristics of Males and Females.

PubMed

Farias Zuniga, Amanda M; Côté, Julie N

2017-06-01

The effects of performing a 90-minute computer task with a laptop versus a dual monitor desktop workstation were investigated in healthy young male and female adults. Work-related musculoskeletal disorders are common among computer (especially female) users. Laptops have surpassed desktop computer sales, and working with multiple monitors has also become popular. However, few studies have provided objective evidence on how they affect the musculoskeletal system in both genders. Twenty-seven healthy participants (mean age = 24.6 years; 13 males) completed a 90-minute computer task while using a laptop or dual monitor (DualMon) desktop. Electromyography (EMG) from eight upper body muscles and visual strain were measured throughout the task. Neck proprioception was tested before and after the computer task using a head-repositioning test. EMG amplitude (root mean square [RMS]), variability (coefficients of variation [CV]), and normalized mutual information (NMI) were computed. Visual strain ( p < .01) and right upper trapezius RMS ( p = .03) increased significantly over time regardless of workstation. Right cervical erector spinae RMS and cervical NMI were smaller, while degrees of overshoot (mean = 4.15°) and end position error (mean = 1.26°) were larger in DualMon regardless of time. Effects on muscle activity were more pronounced in males, whereas effects on proprioception were more pronounced in females. Results suggest that compared to laptop, DualMon work is effective in reducing cervical muscle activity, dissociating cervical connectivity, and maintaining more typical neck repositioning patterns, suggesting some health-protective effects. This evidence could be considered when deciding on computer workstation designs.

Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.

PubMed

Dubé, Marie-Pierre; de Denus, Simon; Tardif, Jean-Claude

2016-02-01

Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.

Computed tomographic findings of pulmonary atelectasis in healthy anesthetized Beagles.

PubMed

le Roux, Christelle; Cassel, Nicolette; Fosgate, Geoffrey T; Zwingenberger, Allison L; Kirberger, Robert M

2016-10-01

OBJECTIVE To characterize the extent and location of atelectasis in healthy anesthetized dogs positioned in lateral recumbency and to determine whether repositioning dogs in sternal recumbency would resolve atelectasis. ANIMALS 6 healthy adult Beagles. PROCEDURES Each dog was anesthetized and underwent a CT examination twice with a 2-week interval between examinations. Once anesthetized, each dog was positioned in sternal recumbency, and a breath-hold helical transverse thoracic CT scan was acquired. The dog was then positioned in lateral recumbency for 30 minutes, and images were obtained at 5 preselected sites at 3, 8, 13, 20, and 30 minutes after repositioning (phase 1). Then, the dog was repositioned in sternal recumbency, and CT images were obtained at the 5 preselected sites at 5, 10, and 20 minutes after repositioning (phase 2). The protocol for the second examination was the same as the first except the dog was positioned in the opposite lateral recumbency during phase 1. The attenuation and cross-sectional area of the lung lobes at the preselected sites were measured and compared over time. RESULTS Lateral recumbency did not cause atelectasis in any of the dogs. Patchy areas of abnormally increased attenuation were infrequently detected in the left cranial lung lobe when dogs were positioned in left lateral recumbency, and those areas failed to resolve when dogs were positioned in sternal recumbency. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent of lung attenuation changes was minimal in healthy anesthetized Beagles positioned in lateral recumbency and should not preclude CT examination.

Learning from Public Television and the Web: Positioning Continuing Education as a Knowledge Portal.

ERIC Educational Resources Information Center

Vedro, Steven R.

1999-01-01

Digital convergence--the merging of television and computing--challenges localized monopolies of public television and continuing education. Continuing educators can reposition themselves in the electronic marketplace by serving as an educational portal, bringing their strengths of "brand recognition," local customer base, and access to…

Novel spirobicyclic artemisinin analogues (artemalogues): Synthesis and antitumor activities.

PubMed

Liu, Gang; Song, Shanshan; Shu, Shiqi; Miao, Zehong; Zhang, Ao; Ding, Chunyong

2015-10-20

The sesquiterpene lactone framework of artemisinin was used as a drug repositioning prototype for the development of novel antitumor drugs. Several series of novel artemisinin analogues (artemalogues) were designed and synthesized through 1,3-dipolar cycloaddition of artemisitene with nitrile oxides or nitrones. The isoxazolidine-containing spirobicyclic artemalogue 11b turns out to be the most potent with low micromolar IC₅₀ values against all three tumor cells, which were at least 4- to 14-fold more potent than the parent artemisinin. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Electromagnetic navigated condylar positioning after high oblique sagittal split osteotomy of the mandible: a guided method to attain pristine temporomandibular joint conditions.

PubMed

Berger, Moritz; Nova, Igor; Kallus, Sebastian; Ristow, Oliver; Eisenmann, Urs; Dickhaus, Hartmut; Engel, Michael; Freudlsperger, Christian; Hoffmann, Jürgen; Seeberger, Robin

2018-05-01

Reproduction of the exact preoperative proximal-mandible position after osteotomy in orthognathic surgery is difficult to achieve. This clinical pilot study evaluated an electromagnetic (EM) navigation system for condylar positioning after high-oblique sagittal split osteotomy (HSSO). After HSSO as part of 2-jaw surgery, the position of 10 condyles was intraoperatively guided by an EM navigation system. As controls, 10 proximal segments were positioned by standard manual replacement. Accuracy was measured by pre- and postoperative cone beam computed tomography imaging. Overall, EM condyle repositioning was equally accurate compared with manual repositioning (P > .05). Subdivided into 3 axes, significant differences could be identified (P < .05). Nevertheless, no significantly and clinically relevant dislocations of the proximal segment of either the EM or the manual repositioning method could be shown (P > .05). This pilot study introduces a guided method for proximal segment positioning after HSSO by applying the intraoperative EM system. The data demonstrate the high accuracy of EM navigation, although manual replacement of the condyles could not be surpassed. However, EM navigation can avoid clinically hidden, severe malpositioning of the condyles. Copyright © 2017 Elsevier Inc. All rights reserved.

Cone-Beam Computed Tomography (CBCT) Versus CT in Lung Ablation Procedure: Which is Faster?

PubMed

Cazzato, Roberto Luigi; Battistuzzi, Jean-Benoit; Catena, Vittorio; Grasso, Rosario Francesco; Zobel, Bruno Beomonte; Schena, Emiliano; Buy, Xavier; Palussiere, Jean

2015-10-01

To compare cone-beam CT (CBCT) versus computed tomography (CT) guidance in terms of time needed to target and place the radiofrequency ablation (RFA) electrode on lung tumours. Patients at our institution who received CBCT- or CT-guided RFA for primary or metastatic lung tumours were retrospectively included. Time required to target and place the RFA electrode within the lesion was registered and compared across the two groups. Lesions were stratified into three groups according to their size (<10, 10-20, >20 mm). Occurrences of electrode repositioning, repositioning time, RFA complications, and local recurrence after RFA were also reported. Forty tumours (22 under CT, 18 under CBCT guidance) were treated in 27 patients (19 male, 8 female, median age 67.25 ± 9.13 years). Thirty RFA sessions (16 under CBCT and 14 under CT guidance) were performed. Multivariable linear regression analysis showed that CBCT was faster than CT to target and place the electrode within the tumour independently from its size (β = -9.45, t = -3.09, p = 0.004). Electrode repositioning was required in 10/22 (45.4 %) tumours under CT guidance and 5/18 (27.8 %) tumours under CBCT guidance. Pneumothoraces occurred in 6/14 (42.8 %) sessions under CT guidance and in 6/16 (37.5 %) sessions under CBCT guidance. Two recurrences were noted for tumours receiving CBCT-guided RFA (2/17, 11.7 %) and three after CT-guided RFA (3/19, 15.8 %). CBCT with live 3D needle guidance is a useful technique for percutaneous lung ablation. Despite lesion size, CBCT allows faster lung RFA than CT.

[Exploiture and application of an internet-based Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine].

PubMed

Xu, Hai-Yu; Liu, Zhen-Ming; Fu, Yan; Zhang, Yan-Qiong; Yu, Jian-Jun; Guo, Fei-Fei; Tang, Shi-Huan; Lv, Chuan-Yu; Su, Jin; Cui, Ru-Yi; Yang, Hong-Jun

2017-09-01

Recently, integrative pharmacology(IP) has become a pivotal paradigm for the modernization of traditional Chinese medicines(TCM) and combinatorial drugs discovery, which is an interdisciplinary science for establishing the in vitro and in vivo correlation between absorption, distribution, metabolism, and excretion/pharmacokinetic(ADME/PK) profiles of TCM and the molecular networks of disease by the integration of the knowledge of multi-disciplinary and multi-stages. In the present study, an internet-based Computation Platform for IP of TCM(TCM-IP, www.tcmip.cn) is established to promote the development of the emerging discipline. Among them, a big data of TCM is an important resource for TCM-IP including Chinese Medicine Formula Database, Chinese Medical Herbs Database, Chemical Database of Chinese Medicine, Target Database for Disease and Symptoms, et al. Meanwhile, some data mining and bioinformatics approaches are critical technology for TCM-IP including the identification of the TCM constituents, ADME prediction, target prediction for the TCM constituents, network construction and analysis, et al. Furthermore, network beautification and individuation design are employed to meet the consumer's requirement. We firmly believe that TCM-IP is a very useful tool for the identification of active constituents of TCM and their involving potential molecular mechanism for therapeutics, which would wildly applied in quality evaluation, clinical repositioning, scientific discovery based on original thinking, prescription compatibility and new drug of TCM, et al. Copyright© by the Chinese Pharmaceutical Association.

Predict drug permeability to blood–brain-barrier from clinical phenotypes: drug side effects and drug indications

PubMed Central

Gao, Zhen; Chen, Yang; Cai, Xiaoshu; Xu, Rong

2017-01-01

Abstract Motivation: Blood–Brain-Barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of Central Nervous System (CNS). Determination of compound’s permeability to BBB is prerequisite in CNS drug discovery. Existing computational methods usually predict drug BBB permeability from chemical structure and they generally apply to small compounds passing BBB through passive diffusion. As abundant information on drug side effects and indications has been recorded over time through extensive clinical usage, we aim to explore BBB permeability prediction from a new angle and introduce a novel approach to predict BBB permeability from drug clinical phenotypes (drug side effects and drug indications). This method can apply to both small compounds and macro-molecules penetrating BBB through various mechanisms besides passive diffusion. Results: We composed a training dataset of 213 drugs with known brain and blood steady-state concentrations ratio and extracted their side effects and indications as features. Next, we trained SVM models with polynomial kernel and obtained accuracy of 76.0%, AUC 0.739, and F1 score (macro weighted) 0.760 with Monte Carlo cross validation. The independent test accuracy was 68.3%, AUC 0.692, F1 score 0.676. When both chemical features and clinical phenotypes were available, combining the two types of features achieved significantly better performance than chemical feature based approach (accuracy 85.5% versus 72.9%, AUC 0.854 versus 0.733, F1 score 0.854 versus 0.725; P < e−90). We also conducted de novo prediction and identified 110 drugs in SIDER database having the potential to penetrate BBB, which could serve as start point for CNS drug repositioning research. Availability and Implementation: https://github.com/bioinformatics-gao/CASE-BBB-prediction-Data Contact: rxx@case.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27993785

Reverse pharmacognosy: another way to harness the generosity of nature.

PubMed

Blondeau, S; Do, Q T; Scior, T; Bernard, P; Morin-Allory, L

2010-05-01

A huge amount of data has been generated by decades of pharmacognosy supported by the rapid evolution of chemical, biological and computational techniques. How can we cope with this overwhelming mass of information? Reverse pharmacognosy was introduced with this aim in view. It proceeds from natural molecules to organisms that contain them via biological assays in order to identify an activity. In silico techniques and particularly inverse screening are key technologies to achieve this goal efficiently. Reverse pharmacognosy allows us to identify which molecule(s) from an organism is(are) responsible for the biological activity and the biological pathway(s) involved. An exciting outcome of this approach is that it not only provides evidence of the therapeutic properties of plants used in traditional medicine for instance, but may also position other plants containing the same active compounds for the same usage, thus increasing the curative arsenal e.g. development of new botanicals. This is particularly interesting in countries where western medicines are still not affordable. At the molecular level, in organisms, families of metabolites are synthesized and seldom have a single structure. Hence, when a natural compound has an interesting activity, it may be desirable to check whether there are more active and/or less toxic derivatives in organisms containing the hit - this corresponds to a kind of "natural combinatorial" chemistry. At a time when the pharmaceutical industry is lacking drug candidates in clinical trials, drug repositioning - i.e. exploiting existing knowledge for innovation - has never been so critical. Reverse pharmacognosy can contribute to addressing certain issues in current drug discovery - such as the lack of clinical candidates, toxicity... - by exploiting existing data from pharmacognosy. This review will focus on recent advances in computer science applied to natural substance research that consolidate the new concept of reverse pharmacognosy.

Drug repurposing and human parasitic protozoan diseases

PubMed Central

Andrews, Katherine T.; Fisher, Gillian; Skinner-Adams, Tina S.

2014-01-01

Parasitic diseases have an enormous health, social and economic impact and are a particular problem in tropical regions of the world. Diseases caused by protozoa and helminths, such as malaria and schistosomiasis, are the cause of most parasite related morbidity and mortality, with an estimated 1.1 million combined deaths annually. The global burden of these diseases is exacerbated by the lack of licensed vaccines, making safe and effective drugs vital to their prevention and treatment. Unfortunately, where drugs are available, their usefulness is being increasingly threatened by parasite drug resistance. The need for new drugs drives antiparasitic drug discovery research globally and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. In this review we discuss one of these approaches, drug repurposing or repositioning, with a focus on major human parasitic protozoan diseases such as malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis. PMID:25057459

Personalized drug discovery: HCA approach optimized for rare diseases at Tel Aviv University.

PubMed

Solmesky, Leonardo J; Weil, Miguel

2014-03-01

The Cell screening facility for personalized medicine (CSFPM) at Tel Aviv University in Israel is devoted to screening small molecules libraries for finding new drugs for rare diseases using human cell based models. The main strategy of the facility is based on smartly reducing the size of the compounds collection in similarity clusters and at the same time keeping high diversity of pharmacophores. This strategy allows parallel screening of several patient derived - cells in a personalized screening approach. The tested compounds are repositioned drugs derived from collections of phase III and FDA approved small molecules. In addition, the facility carries screenings using other chemical libraries and toxicological characterizations of nanomaterials.

Evaluation of methylene blue, pyrimethamine and its combination on an in vitro Neospora caninum model.

PubMed

Pereira, Luiz Miguel; Vigato-Ferreira, Isabel Cristina; DE Luca, Gabriela; Bronzon DA Costa, Cássia Mariana; Yatsuda, Ana Patrícia

2017-05-01

Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low-cost therapeutics approaches against neosporosis.

Identification of novel drug targets in bovine respiratory disease: an essential step in applying biotechnologic techniques to develop more effective therapeutic treatments

PubMed Central

Sakharkar, Meena Kishore; Rajamanickam, Karthic; Chandra, Ramesh; Khan, Haseeb A; Alhomida, Abdullah S; Yang, Jian

2018-01-01

Background Bovine Respiratory Disease (BRD) is a major problem in cattle production which causes substantial economic loss. BRD has multifactorial aetiologies, is multi-microbial, and several of the causative pathogens are unknown. Consequently, primary management practices such as metaphylactic antimicrobial injections for BRD prevention are used to reduce the incidence of BRD in feedlot cattle. However, this poses a serious threat in the form of development of antimicrobial resistance and demands an urgent need to find novel interventions that could reduce the effects of BRD drastically and also delay/prevent bacterial resistance. Materials and methods We have employed a subtractive genomics approach that helps delineate essential, host-specific, and druggable targets in pathogens responsible for BRD. We also proposed antimicrobials from FDA green and orange book that could be repositioned for BRD. Results We have identified 107 putative targets that are essential, selective and druggable. We have also confirmed the susceptibility of two BRD pathogens to one of the proposed antimicrobials – oxytetracycline. Conclusion This approach allows for repositioning drugs known for other infections to BRD, predicting novel druggable targets for BRD infection, and providing a new direction in developing more effective therapeutic treatments for BRD. PMID:29765203

An economic analysis of repositioning for the prevention of pressure ulcers.

PubMed

Moore, Zena; Cowman, Seamus; Posnett, John

2013-08-01

To compare pressure ulcer incidence and costs associated with repositioning older individuals in long-term care using two different repositioning regimes. Repositioning has not always been integrated into pressure ulcer preventative methods, with arguments that it is an expensive procedure in terms of personnel and time. Participants were randomly allocated to the experimental group (n = 99; repositioned every 3 hours, using the 30° tilt) and the control group (n = 114 standard care, repositioned every 6 hours, using the 90° lateral rotation). The analysis explored the incidence of pressure ulcer development and the cost difference between the two repositioning schedules, over a 4-week period. The mean daily nurse time for repositioning was 18·5 minutes (experimental) and 24·5 minutes (control). Nurse time cost per patient over the study period was €206·6 (experimental) and €253·1 (control), 96·6% of participants (experimental) remained free of pressure ulcers, compared with 88·1% (control). The cost per patient free of ulcer was €213·9 (experimental) and €287·3 (control). Projected annual costs were estimated for the 588 (53·5%) residents in the 12 study sites requiring repositioning. The cost would be €1·59 m (experimental) and €2·10 m (control), a cost difference of €510,000. This represents a difference of 58·8 hours of nurse time, equivalent to approximately 12 full time nurses across the 12 sites. Repositioning every 3 hours, using 30° tilt, has been shown to be more effective in less costly in terms of nurse time compared with standard care. Repositioning individuals at risk of pressure ulcer development makes both economic and clinical sense, thereby supporting the EPUAP/NPUAP 2009 guidelines. © 2013 John Wiley & Sons Ltd.

Effect of a Patient-Repositioning Device in an Intensive Care Unit On Hospital-Acquired Pressure Injury Occurences and Cost: A Before-After Study.

PubMed

Edger, Melinda

The principal aim of this study was to determine the hospital-acquired pressure injury (HAPI) rate before and after introduction of a repositioning device, measure staff-perceived level of exertion with device use, and assess return on investment. 1 group, before-and-after study. The sample comprised 717 patients cared for in a 17-bed intensive care unit. The study setting was the neonatal intensive care unit at Bon Secours Maryview Medical Center located in the mid-Atlantic United States (Portsmouth, Virginia). A safe patient-handling intervention was implemented as part of a quality improvement initiative. The effect of this system was measured using several outcome measures: (1) HAPI occurrences on the sacral area and buttocks, (2) perceived effort of use by staff, and (3) cost analysis. We used the validated Borg Scale to measure perceived exertion that was ranked on a scale from 6 to 20, where higher scores indicate greater exertion. Cost comparisons were completed before and after introduction of the patient-repositioning system. Cost analysis was determined using internal dollar amounts calculated for each stage of pressure injury. The return on investment was calculated by comparing the cost of HAPIs and the product after the intervention with the costs of HAPIs before the intervention. Analysis revealed a statistically significant reduction in HAPI occurrence from 1.3% to 0% (P = .004) when baseline manual repositioning (standard of care) was compared with use of the repositioning system. Caregivers reported significantly less exertion when using the repositioning device as compared with standard of care repositioning (P < .001). The return on investment was estimated to be $16,911. Use of a repositioning device resulted in significantly reduced HAPIs. Perceived exertion for repositioning the patient with a repositioning device was significantly less than repositioning with standard of care. A cost analysis estimated a return on investment as a result of the intervention on HAPI prevention.

Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on the Management of Patients With Positional Plagiocephaly: The Role of Repositioning.

PubMed

Klimo, Paul; Lingo, Patrick Ryan; Baird, Lissa C; Bauer, David F; Beier, Alexandra; Durham, Susan; Lin, Alexander Y; McClung-Smith, Catherine; Mitchell, Laura; Nikas, Dimitrios; Tamber, Mandeep S; Tyagi, Rachana; Mazzola, Catherine; Flannery, Ann Marie

2016-11-01

Plagiocephaly, involving positional deformity of the calvarium in infants, is one of the most common reasons for pediatric neurosurgical consultation. To answer the question: "what is the evidence for the effectiveness of repositioning for positional plagiocephaly?" Treatment recommendations are provided based on the available evidence. The National Library of Medicine MEDLINE database and the Cochrane Library were queried using MeSH headings and key words relevant to repositioning as a means to treat plagiocephaly and brachycephaly. Abstracts were reviewed to identify which studies met the inclusion criteria. An evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). There were 3 randomized trials (Class I), 1 prospective cohort study (Class II), and 6 retrospective cohort studies (Class III). Repositioning education was found to be equal to a repositioning device and inferior to a physical therapy program. Five of the 7 cohort studies comparing repositioning with a helmet reported helmets to be better and take less time. Within the limits of this systematic review, repositioning education is effective in affording some degree of correction in virtually all infants with positional plagiocephaly or brachycephaly. Most studies suggest that a molding helmet corrects asymmetry more rapidly and to a greater degree than repositioning education. In a Class I study, repositioning education was as effective as repositioning education in conjunction with a repositioning wrap/device. Another Class I study demonstrated that a bedding pillow was superior to physical therapy for some infants. However, in keeping with the American Academy of Pediatrics' warning against the use of soft positioning pillows in the sleeping environment, the Task Force recommends physical therapy over any positioning device. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional-plagiocephaly/Chapter_3.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on the Management of Patients With Positional Plagiocephaly: The Role of Repositioning.

PubMed

Klimo, Paul; Lingo, Patrick Ryan; Baird, Lissa C; Bauer, David F; Beier, Alexandra; Durham, Susan; Lin, Alexander Y; McClung-Smith, Catherine; Mitchell, Laura; Nikas, Dimitrios; Tamber, Mandeep S; Tyagi, Rachana; Mazzola, Catherine; Flannery, Ann Marie

2016-11-01

Plagiocephaly, involving positional deformity of the calvarium in infants, is one of the most common reasons for pediatric neurosurgical consultation. To answer the question: "what is the evidence for the effectiveness of repositioning for positional plagiocephaly?" Treatment recommendations are provided based on the available evidence. The National Library of Medicine MEDLINE database and the Cochrane Library were queried using MeSH headings and key words relevant to repositioning as a means to treat plagiocephaly and brachycephaly. Abstracts were reviewed to identify which studies met the inclusion criteria. An evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). There were 3 randomized trials (Class I), 1 prospective cohort study (Class II), and 6 retrospective cohort studies (Class III). Repositioning education was found to be equal to a repositioning device and inferior to a physical therapy program. Five of the 7 cohort studies comparing repositioning with a helmet reported helmets to be better and take less time. Within the limits of this systematic review, repositioning education is effective in affording some degree of correction in virtually all infants with positional plagiocephaly or brachycephaly. Most studies suggest that a molding helmet corrects asymmetry more rapidly and to a greater degree than repositioning education. In a Class I study, repositioning education was as effective as repositioning education in conjunction with a repositioning wrap/device. Another Class I study demonstrated that a bedding pillow was superior to physical therapy for some infants. However, in keeping with the American Academy of Pediatrics' warning against the use of soft positioning pillows in the sleeping environment, the Task Force recommends physical therapy over any positioning device. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional-plagiocephaly/Chapter_3.

Head repositioning accuracy in patients with whiplash-associated disorders.

PubMed

Feipel, Veronique; Salvia, Patrick; Klein, Helene; Rooze, Marcel

2006-01-15

Controlled study, measuring head repositioning error (HRE) using an electrogoniometric device. To compare HRE in neutral position, axial rotation and complex postures of patients with whiplash-associated disorders (WAD) to that of control subjects. The presence of kinesthetic alterations in patients with WAD is controversial. In 26 control subjects and 29 patients with WAD (aged 22-74 years), head kinematics was sampled using a 3-dimensional electrogoniometer mounted using a harness and a helmet. All tasks were realized in seated position. The repositioning tasks included neutral repositioning after maximal flexion-extension, eyes open and blindfolded, repositioning at 50 degrees of axial rotation, and repositioning at 50 degrees of axial rotation combined to 20 degrees of ipsilateral bending. The flexion-extension, ipsilateral bending, and axial rotation components of HRE were considered. A multiple-way repeated-measures analysis of variance was used to compare tasks and groups. The WAD group displayed a reduced flexion-extension range (P = 1.9 x 10(-4)), and larger HRE during flexion-extension and repositioning tasks (P = 0.009) than controls. Neither group nor task affected maximal motion velocity. Neutral HRE of the flexion-extension component was larger in blindfolded condition (P = 0.03). Ipsilateral bending and axial rotation HRE components were smaller than the flexion-extension component (P = 7.1 x 10(-23)). For pure rotation repositioning, axial rotation HRE was significantly larger than flexion-extension and ipsilateral bending repositioning error (P = 3.0 x 10(-23)). Ipsilateral bending component of HRE was significantly larger combined tasks than for pure rotation tasks (P = 0.004). In patients with WAD, range of motion and head repositioning accuracy were reduced. However, the differences were small. Vision suppression and task type influenced HRE.

The opportunities of mining historical and collective data in drug discovery.

PubMed

Wassermann, Anne Mai; Lounkine, Eugen; Davies, John W; Glick, Meir; Camargo, L Miguel

2015-04-01

Vast amounts of bioactivity data have been generated for small molecules across public and corporate domains. Biological signatures, either derived from systematic profiling efforts or from existing historical assay data, have been successfully employed for small molecule mechanism-of-action elucidation, drug repositioning, hit expansion and screening subset design. This article reviews different types of biological descriptors and applications, and we demonstrate how biological data can outlive the original purpose or project for which it was generated. By comparing 150 HTS campaigns run at Novartis over the past decade on the basis of their active and inactive chemical matter, we highlight the opportunities and challenges associated with cross-project learning in drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protein Kinases and Parkinson's Disease.

PubMed

Mehdi, Syed Jafar; Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Barger, Steven W; Sarkar, Sumit; Paule, Merle G; Ali, Syed F; Imam, Syed Z

2016-09-20

Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson's disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson's disease. This review focuses on various kinase-dependent pathways associated with the expression of Parkinson's disease pathology, and evaluates how inhibitors of these pathways might play a major role as effective therapeutic molecules.

Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

PubMed

Cheng, Feixiong; Murray, James L; Zhao, Junfei; Sheng, Jinsong; Zhao, Zhongming; Rubin, Donald H

2016-09-01

Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

An application framework for computer-aided patient positioning in radiation therapy.

PubMed

Liebler, T; Hub, M; Sanner, C; Schlegel, W

2003-09-01

The importance of exact patient positioning in radiation therapy increases with the ongoing improvements in irradiation planning and treatment. Therefore, new ways to overcome precision limitations of current positioning methods in fractionated treatment have to be found. The Department of Medical Physics at the German Cancer Research Centre (DKFZ) follows different video-based approaches to increase repositioning precision. In this context, the modular software framework FIVE (Fast Integrated Video-based Environment) has been designed and implemented. It is both hardware- and platform-independent and supports merging position data by integrating various computer-aided patient positioning methods. A highly precise optical tracking system and several subtraction imaging techniques have been realized as modules to supply basic video-based repositioning techniques. This paper describes the common framework architecture, the main software modules and their interfaces. An object-oriented software engineering process has been applied using the UML, C + + and the Qt library. The significance of the current framework prototype for the application in patient positioning as well as the extension to further application areas will be discussed. Particularly in experimental research, where special system adjustments are often necessary, the open design of the software allows problem-oriented extensions and adaptations.

New Antimicrobial Approaches: Reuse of Old Drugs.

PubMed

Savoia, Dianella

2016-01-01

The global situation of antibiotic resistance and the reduction of investments in antibiotics research by the pharmaceutical industry suggest the need for specific cost-effective approaches in order to identify drugs for the therapy of many microbial infections. Among the viable alternative anti-infective compounds, drug repurposing, i.e. to find new uses for previously approved medicines, revealed some encouraging in vitro and in vivo results. In this article the reader has a panoramic view of the updated references on the strategies encountered during the repositioning process. New findings are reported about the anti-microbial efficacy of antipsychotic, cardiovascular, anti-inflammatory and anti-neoplastic drugs. This approach may enhance the portfolio of pharmaceutical companies reducing the need for pharmacokinetic and toxicity studies; the development of new uses of old drugs for different infectious diseases, leading to better health for patients, also in poor, tropical countries, appears to be having better results.

Ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China.

PubMed

Wang, Mei; Wang, Hongxia; Zhao, Namula

2015-02-01

To explore the unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China. Based on the natural life concept of "integration of universe and man", osteopathy in traditional Mongolian medicine in China uses the modern principles and methods of physiology, psychology, and biomechanics. Against this background, we explored the unique ideas, properties, and stan- dards of fracture repositioning in traditional Mongolian medicine. Fracture treatment with osteopathy in traditional Mongolian medicine in China is based on (a) the ideas of natural, sealed, self and dynamic repositioning of fractures; (b) the properties of structural continuity and functional completeness; (c) the standards of "integration of movement and stillness" and "force to force". The unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China have resulted in the widespread use of such techniques and represents the future direction of the development of fracture repositioning.

Clinical feasibility and efficacy of using virtual surgical planning in bimaxillary orthognathic surgery without intermediate splint.

PubMed

Li, Yunfeng; Jiang, Yangmei; Zhang, Nan; Xu, Rui; Hu, Jing; Zhu, Songsong

2015-03-01

Computer-aided jaw surgery has been extensively studied recently. The purpose of this study was to determine the clinical feasibility of performing bimaxillary orthognathic surgery without intermediate splint using virtual surgical planning and rapid prototyping technology. Twelve consecutive patients who underwent bimaxillary orthognathic surgery were included. The presented treatment plan here mainly consists of 6 procedures: (1) data acquisition from computed tomography (CT) of the skull and laser scanning of the dentition; (2) reconstruction and fusion of a virtual skull model with accurate dentition; (3) virtual surgery simulation including osteotomy and movement and repositioning of bony segments; (4) final surgical splint fabrication (no intermediate splint) using computer-aided design and rapid prototyping technology; (5) transfer of the virtual surgical plan to the operating room; and (6) comparison of the actual surgical outcome to the virtual surgical plan. All procedures of the treatment were successfully performed on all 12 patients. In quantification of differences between simulated and actual postoperative outcome, we found that the mean linear difference was less than 1.8 mm, and the mean angular difference was less than 2.5 degrees in all evaluated patients. Results from this study suggested that it was feasible to perform bimaxillary orthognathic surgery without intermediate splint. Virtual surgical planning and the guiding splints facilitated the diagnosis, treatment planning, accurate osteotomy, and bony segments repositioning in orthognathic surgery.

Three-dimensional repositioning accuracy of semiadjustable articulator cast mounting systems.

PubMed

Tan, Ming Yi; Ung, Justina Youlin; Low, Ada Hui Yin; Tan, En En; Tan, Keson Beng Choon

2014-10-01

In spite of its importance in prosthesis precision and quality, the 3-dimensional repositioning accuracy of cast mounting systems has not been reported in detail. The purpose of this study was to quantify the 3-dimensional repositioning accuracy of 6 selected cast mounting systems. Five magnetic mounting systems were compared with a conventional screw-on system. Six systems on 3 semiadjustable articulators were evaluated: Denar Mark II with conventional screw-on mounting plates (DENSCR) and magnetic mounting system with converter plates (DENCON); Denar Mark 330 with in-built magnetic mounting system (DENMAG) and disposable mounting plates; and Artex CP with blue (ARTBLU), white (ARTWHI), and black (ARTBLA) magnetic mounting plates. Test casts with 3 high-precision ceramic ball bearings at the mandibular central incisor (Point I) and the right and left second molar (Point R; Point L) positions were mounted on 5 mounting plates (n=5) for all 6 systems. Each cast was repositioned 10 times by 4 operators in random order. Nine linear (Ix, Iy, Iz; Rx, Ry, Rz; Lx, Ly, Lz) and 3 angular (anteroposterior, mediolateral, twisting) displacements were measured with a coordinate measuring machine. The mean standard deviations of the linear and angular displacements defined repositioning accuracy. Anteroposterior linear repositioning accuracy ranged from 23.8 ±3.7 μm (DENCON) to 4.9 ±3.2 μm (DENSCR). Mediolateral linear repositioning accuracy ranged from 46.0 ±8.0 μm (DENCON) to 3.7 ±1.5 μm (ARTBLU), and vertical linear repositioning accuracy ranged from 7.2 ±9.6 μm (DENMAG) to 1.5 ±0.9 μm (ARTBLU). Anteroposterior angular repositioning accuracy ranged from 0.0084 ±0.0080 degrees (DENCON) to 0.0020 ±0.0006 degrees (ARTBLU), and mediolateral angular repositioning accuracy ranged from 0.0120 ±0.0111 degrees (ARTWHI) to 0.0027 ±0.0008 degrees (ARTBLU). Twisting angular repositioning accuracy ranged from 0.0419 ±0.0176 degrees (DENCON) to 0.0042 ±0.0038 degrees (ARTBLA). One-way ANOVA found significant differences (P<.05) among all systems for Iy, Ry, Lx, Ly, and twisting. Generally, vertical linear displacements were less likely to reach the threshold of clinical detectability compared with anteroposterior or mediolateral linear displacements. The overall repositioning accuracy of DENSCR was comparable with 4 magnetic mounting systems (DENMAG, ARTBLU, ARTWHI, ARTBLA). DENCON exhibited the worst repositioning accuracy for Iy, Ry, Lx, Ly, and twisting. Copyright © 2014 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Designing Dietary Recommendations Using System Level Interactomics Analysis and Network-Based Inference

PubMed Central

Zheng, Tingting; Ni, Yueqiong; Li, Jun; Chow, Billy K. C.; Panagiotou, Gianni

2017-01-01

Background: A range of computational methods that rely on the analysis of genome-wide expression datasets have been developed and successfully used for drug repositioning. The success of these methods is based on the hypothesis that introducing a factor (in this case, a drug molecule) that could reverse the disease gene expression signature will lead to a therapeutic effect. However, it has also been shown that globally reversing the disease expression signature is not a prerequisite for drug activity. On the other hand, the basic idea of significant anti-correlation in expression profiles could have great value for establishing diet-disease associations and could provide new insights into the role of dietary interventions in disease. Methods: We performed an integrated analysis of publicly available gene expression profiles for foods, diseases and drugs, by calculating pairwise similarity scores for diet and disease gene expression signatures and characterizing their topological features in protein-protein interaction networks. Results: We identified 485 diet-disease pairs where diet could positively influence disease development and 472 pairs where specific diets should be avoided in a disease state. Multiple evidence suggests that orange, whey and coconut fat could be beneficial for psoriasis, lung adenocarcinoma and macular degeneration, respectively. On the other hand, fructose-rich diet should be restricted in patients with chronic intermittent hypoxia and ovarian cancer. Since humans normally do not consume foods in isolation, we also applied different algorithms to predict synergism; as a result, 58 food pairs were predicted. Interestingly, the diets identified as anti-correlated with diseases showed a topological proximity to the disease proteins similar to that of the corresponding drugs. Conclusions: In conclusion, we provide a computational framework for establishing diet-disease associations and additional information on the role of diet in disease development. Due to the complexity of analyzing the food composition and eating patterns of individuals our in silico analysis, using large-scale gene expression datasets and network-based topological features, may serve as a proof-of-concept in nutritional systems biology for identifying diet-disease relationships and subsequently designing dietary recommendations. PMID:29033850

Inferring drug-disease associations based on known protein complexes.

PubMed

Yu, Liang; Huang, Jianbin; Ma, Zhixin; Zhang, Jing; Zou, Yapeng; Gao, Lin

2015-01-01

Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html.

Inferring drug-disease associations based on known protein complexes

PubMed Central

2015-01-01

Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html. PMID:26044949

Deep-Learning-Based Drug-Target Interaction Prediction.

PubMed

Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

2017-04-07

Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

[Application of the dizziness handicap inventory in the patients with benign paroxysmal positional vertigo].

PubMed

Wang, L Y; Peng, H; Huang, W N; Gao, B

2016-04-20

Objective: This study was designed to observe the dizziness handicap inventory (DHI) scores in patients with BPPV (benign paroxysmal positional vertigo) before and after maneuver repositioning and aimed to discuss the values of DHI scores in the diagnosing and treatment of BPPV. Method: Charts of 72 patients with BPPV diagnosed by positioning test were reviewed. Four DHI scores were used including the total score (DHIT), the functional score (DHIF), the emotional score (DHIE), and the physical score (DHIP). We compared the pre-repositioning DHI scores and post-repositioning scores of patients, and also compared the DHI scores of patients with and without residual dizziness. Result: All of the 72 patients were underwent maneuver repositioning and recorded the DHI scores. The mean post-repositioning scores were dramatically decreased compared with pre-repositioning scores, and the difference was significant ( P <0.01). The differences of the DHIP scores between the residual dizziness group and the non-residual dizziness group was not significant, while the DHIF scores, the DHIE scores and the DHIT scores between the two groups were statistically different. Conclusion: After maneuver repositioning the dizziness handicap of BPPV patients could be significantly improved. The next treatment program for residual dizziness patients after successful repositioning could be aimed at the functional and emotional dizziness. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

Repositioning for pressure ulcer prevention in adults.

PubMed

Gillespie, Brigid M; Chaboyer, Wendy P; McInnes, Elizabeth; Kent, Bridie; Whitty, Jennifer A; Thalib, Lukman

2014-04-03

A pressure ulcer (PU), also referred to as a 'pressure injury', 'pressure sore', or 'bedsore' is defined as an area of localised tissue damage that is caused by unrelieved pressure, friction or shearing forces on any part of the body. PUs commonly occur in patients who are elderly and less mobile, and carry significant human and economic impacts. Immobility and physical inactivity are considered to be major risk factors for PU development and the manual repositioning of patients in hospital or long-term care is a common pressure ulcer prevention strategy. The objectives of this review were to:1) assess the effects of repositioning on the prevention of PUs in adults, regardless of risk or in-patient setting;2) ascertain the most effective repositioning schedules for preventing PUs in adults; and3) ascertain the incremental resource consequences and costs associated with implementing different repositioning regimens compared with alternate schedules or standard practice. We searched the following electronic databases to identify reports of the relevant randomised controlled trials: the Cochrane Wounds Group Specialised Register (searched 06 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 8); Ovid MEDLINE (1948 to August, Week 4, 2013); Ovid EMBASE (1974 to 2013, Week 35); EBESCO CINAHL (1982 to 30 August 2013); and the reference sections of studies that were included in the review. Randomised controlled trials (RCTs), published or unpublished, that assessed the effects of any repositioning schedule or different patient positions and measured PU incidence in adults in any setting. Two review authors independently performed study selection, risk of bias assessment and data extraction. We included three RCTs and one economic study representing a total of 502 randomised participants from acute and long-term care settings. Two trials compared the 30º and 90º tilt positions using similar repositioning frequencies (there was a small difference in frequency of overnight repositioning in the 90º tilt groups between the trials). The third RCT compared alternative repositioning frequencies.All three studies reported the proportion of patients developing PU of any grade, stage or category. None of the trials reported on pain, or quality of life, and only one reported on cost. All three trials were at high risk of bias.The two trials of 30º tilt vs. 90º were pooled using a random effects model (I² = 69%) (252 participants). The risk ratio for developing a PU in the 30º tilt and the standard 90º position was very imprecise (pooled RR 0.62, 95% CI 0.10 to 3.97, P=0.62, very low quality evidence). This comparison is underpowered and at risk of a Type 2 error (only 21 events).In the third study, a cluster randomised trial, participants were randomised between 2-hourly and 3-hourly repositioning on standard hospital mattresses and 4 hourly and 6 hourly repositioning on viscoelastic foam mattresses. This study was also underpowered and at high risk of bias. The risk ratio for pressure ulcers (any category) with 2-hourly repositioning compared with 3-hourly repositioning on a standard mattress was imprecise (RR 0.90, 95% CI 0.69 to 1.16, very low quality evidence). The risk ratio for pressure ulcers (any category) was compatible with a large reduction and no difference between 4-hourly repositioning and 6-hourly repositioning on viscoelastic foam (RR 0.73, 95% CI 0.53 to 1.02, very low quality evidence).A cost-effectiveness analysis based on data derived from one of the included parallel RCTs compared 3-hourly repositioning using the 30º tilt overnight with standard care consisting of 6-hourly repositioning using the 90º lateral rotation overnight. In this evaluation the only included cost was nursing time. The intervention was reported to be cost saving compared with standard care (nurse time cost per patient €206.6 vs €253.1, incremental difference €-46.5; 95%CI: €-1.25 to €-74.60). Repositioning is an integral component of pressure ulcer prevention and treatment; it has a sound theoretical rationale, and is widely recommended and used in practice. The lack of robust evaluations of repositioning frequency and position for pressure ulcer prevention mean that great uncertainty remains but it does not mean these interventions are ineffective since all comparisons are grossly underpowered. Current evidence is small in volume and at risk of bias and there is currently no strong evidence of a reduction in pressure ulcers with the 30° tilt compared with the standard 90º position or good evidence of an effect of repositioning frequency. There is a clear need for high-quality, adequately-powered trials to assess the effects of position and optimal frequency of repositioning on pressure ulcer incidence.The limited data derived from one economic evaluation means it remains unclear whether repositioning every 3 hours using the 30º tilt is less costly in terms of nursing time and more effective than standard care involving repositioning every 6 hours using a 90º tilt.

Decisions on repositioning of intruded permanent incisors; a review and case presentation.

PubMed

Hurley, E; Stewart, C; Gallagher, C; Kinirons, M

2018-06-01

Traumatic intrusion is a luxation type of injury where the tooth is displaced along the axis of the tooth, into the alveolus. This injury is regarded as serious because of the tissue damage that it causes. The traumatic movement is associated with severe damage to the periodontal ligament, pulpal tissue, root and alveolar socket. Despite its severity, the rare occurrence of this injury in permanent teeth has resulted in limited studies of immature and mature permanent incisors. The purpose of this paper is to review this luxation injury of permanent immature incisors, and to describe its diagnosis, treatment and management. In particular, we describe the repositioning strategies used in cases of intrusion injury. These include (i) monitoring spontaneous re-eruption, (ii) active orthodontic repositioning and (iii) surgical repositioning. Firstly, monitoring spontaneous re-eruption is observing and waiting for the intruded tooth to return to its original position. This process is not a normal developmental eruption and the outcome is not always predictable, nor is the time needed for this to happen. Secondly, active orthodontic repositioning is used to describe the process of rapidly moving the intruded tooth to its original position with the aid of an orthodontic appliance. Active orthodontic repositioning is often misunderstood as normal orthodontic movement. Orthodontic movement allows for periodontal ligament remodelling, using light intermittent forces. In contrast the active orthodontic repositioning used to move intruded incisors is rapid, and the primary aim is to achieve correct tooth position as rapidly as possible. Thirdly, surgical repositioning uses surgical intervention to bring the tooth back to its original position. A case of an intruded immature permanent incisor is presented, with a particular emphasis on these critical decisions on repositioning and showing the use of the three modalities of treatment in sequence, in order to achieve an outcome.

The extraction of drug-disease correlations based on module distance in incomplete human interactome.

PubMed

Yu, Liang; Wang, Bingbo; Ma, Xiaoke; Gao, Lin

2016-12-23

Extracting drug-disease correlations is crucial in unveiling disease mechanisms, as well as discovering new indications of available drugs, or drug repositioning. Both the interactome and the knowledge of disease-associated and drug-associated genes remain incomplete. We present a new method to predict the associations between drugs and diseases. Our method is based on a module distance, which is originally proposed to calculate distances between modules in incomplete human interactome. We first map all the disease genes and drug genes to a combined protein interaction network. Then based on the module distance, we calculate the distances between drug gene sets and disease gene sets, and take the distances as the relationships of drug-disease pairs. We also filter possible false positive drug-disease correlations by p-value. Finally, we validate the top-100 drug-disease associations related to six drugs in the predicted results. The overlapping between our predicted correlations with those reported in Comparative Toxicogenomics Database (CTD) and literatures, and their enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways demonstrate our approach can not only effectively identify new drug indications, but also provide new insight into drug-disease discovery.

Hologram repositioning by an interferometric technique.

PubMed

Soares, O D

1979-11-15

An interferometric technique for hologram repositioning is described where the hologram is compared with the interference pattern of the reference and object waves. Analytical expressions to evaluate the accuracy of the repositioning are presented for the method. Two applications of the method in metrology for micromovement measurements are proposed.

Predicting drug-disease interactions by semi-supervised graph cut algorithm and three-layer data integration.

PubMed

Wu, Guangsheng; Liu, Juan; Wang, Caihua

2017-12-28

Prediction of drug-disease interactions is promising for either drug repositioning or disease treatment fields. The discovery of novel drug-disease interactions, on one hand can help to find novel indictions for the approved drugs; on the other hand can provide new therapeutic approaches for the diseases. Recently, computational methods for finding drug-disease interactions have attracted lots of attention because of their far more higher efficiency and lower cost than the traditional wet experiment methods. However, they still face several challenges, such as the organization of the heterogeneous data, the performance of the model, and so on. In this work, we present to hierarchically integrate the heterogeneous data into three layers. The drug-drug and disease-disease similarities are first calculated separately in each layer, and then the similarities from three layers are linearly fused into comprehensive drug similarities and disease similarities, which can then be used to measure the similarities between two drug-disease pairs. We construct a novel weighted drug-disease pair network, where a node is a drug-disease pair with known or unknown treatment relation, an edge represents the node-node relation which is weighted with the similarity score between two pairs. Now that similar drug-disease pairs are supposed to show similar treatment patterns, we can find the optimal graph cut of the network. The drug-disease pair with unknown relation can then be considered to have similar treatment relation with that within the same cut. Therefore, we develop a semi-supervised graph cut algorithm, SSGC, to find the optimal graph cut, based on which we can identify the potential drug-disease treatment interactions. By comparing with three representative network-based methods, SSGC achieves the highest performances, in terms of both AUC score and the identification rates of true drug-disease pairs. The experiments with different integration strategies also demonstrate that considering several sources of data can improve the performances of the predictors. Further case studies on four diseases, the top-ranked drug-disease associations have been confirmed by KEGG, CTD database and the literature, illustrating the usefulness of SSGC. The proposed comprehensive similarity scores from multi-views and multiple layers and the graph-cut based algorithm can greatly improve the prediction performances of drug-disease associations.

Effects of HO-/MeO-PBDEs on androgen receptor: in vitro investigation and helix 12-involved MD simulation.

PubMed

Wang, Xiaoxiang; Yang, Huaiyu; Hu, Xinxin; Zhang, Xiaowei; Zhang, Qiansen; Jiang, Hualiang; Shi, Wei; Yu, Hongxia

2013-10-15

Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants.

Digital Mammography with a Mosaic of CCD Arrays

NASA Technical Reports Server (NTRS)

Jalink, Antony, Jr. (Inventor); McAdoo, James A. (Inventor)

1998-01-01

A digital mammography device uses a mosaic of electronic digital imaging arrays to scan an x-ray image is discussed. The mosaic of arrays is repositioned several times to expose different portions of the image, until the entire image is scanned. The data generated by the arrays during each exposure is stored in a computer. After the final exposure, the computer combines data of the several partial images to produce a composite of the original x-ray image. An aperture plate is used to reduce scatter and the overall exposure of the patient to x-rays.

Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing.

PubMed

Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

2016-09-07

Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications.

Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

PubMed Central

Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

2016-01-01

Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

Targeting FASN for Breast Cancer Treatment by Repositioning PPIs

DTIC Science & Technology

2017-01-01

the sole cytosolic enzyme responsible for de novo synthesis of palmitate. Recently, it was found that FASN up-regulation contributes to drug and...increased whereas Flag-p65 (NF-κB) over-expression significantly reduced PARP-1 protein and mRNA levels. Knocking down p65 using shRNA significantly...increased PARP-1 protein and mRNA levels (Fig. 2C), whereas activation of p65 with TNF-α had contrary effect (Fig. 2D). Taken together, these results

Effects of over-the-counter jaw-repositioning mouth guards on dynamic balance, flexibility, agility, strength, and power in college-aged male athletes.

PubMed

Golem, Devon L; Arent, Shawn M

2015-02-01

Improvements in muscular power and anaerobic performance have resulted from the use of jaw-repositioning mouth guards designed with advanced dental techniques. The high cost of such techniques has dissuaded the widespread use. Recently, more affordable, over-the-counter (OTC) jaw-repositioning mouth guards have become available. The primary objective of this study was to examine the effects of 2 OTC jaw-repositioning mouth guards on muscular power and strength performance in college-aged male athletes. It was hypothesized that similar to previous observations with advanced dentistry-designed mouth guards, OTC jaw-repositioning mouth guards would impart positive effects on muscular power but not have any effect on muscular strength. Secondary objectives of this study included the examination of the effects of 2 OTC jaw-repositioning mouth guards on other variables related to athletic performance. Male collegiate athletes (N = 20) participated in 4 separate testing sessions that consisted of assessment of muscular power, dynamic balance, flexibility, agility, and muscular strength. The 4 conditions, 1 per testing session, were assigned in a randomized order and consisted of a no-mouth guard control (CON), a placebo mouth guard, a self-adapted jaw-repositioning mouth guard (SA), and a custom-fitted jaw-repositioning mouth guard (CF). No significant differences were observed between conditions in muscular power (p = 0.78), dynamic balance (p = 0.99), agility (p = 0.22), or muscular strength (p = 0.47). The CF had significantly lower hip flexion than the CON (p = 0.014) and had significantly greater lumbar spine lateral flexion compared with the SA condition (p = 0.054). However, these flexibility differences lack practical relevance as the effect sizes remain very small (ES = -0.27 and -0.14, respectively). In conclusion, the jaw-repositioning technique used in the design of these OTC mouth guards did not affect performance. It is important to note that negative effects were not observed indicating that mouth guard use did not impede performance.

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

PubMed Central

Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Paccez, Juliano Domiraci; Borges, Clayton Luiz

2017-01-01

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs. PMID:28694566

Margin reduction from image guided radiation therapy for soft tissue sarcoma: Secondary analysis of Radiation Therapy Oncology Group 0630 results.

PubMed

Li, X Allen; Chen, Xiaojian; Zhang, Qiang; Kirsch, David G; Petersen, Ivy; DeLaney, Thomas F; Freeman, Carolyn R; Trotti, Andy; Hitchcock, Ying; Bedi, Meena; Haddock, Michael; Salerno, Kilian; Dundas, George; Wang, Dian

2016-01-01

Six imaging modalities were used in Radiation Therapy Oncology Group (RTOG) 0630, a study of image guided radiation therapy (IGRT) for primary soft tissue sarcomas of the extremity. We analyzed all daily patient-repositioning data collected in this trial to determine the impact of daily IGRT on clinical target volume-to-planning target volume (CTV-to-PTV) margin. Daily repositioning data, including shifts in right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions and rotations for 98 patients enrolled in RTOG 0630 from 18 institutions were analyzed. Patients were repositioned daily on the basis of bone anatomy by using pretreatment images, including kilovoltage orthogonal images (KVorth), megavoltage orthogonal images (MVorth), KV fan-beam computed tomography (KVCT), KV cone beam CT (KVCB), MV fan-beam CT (MVCT), and MV cone beam CT (MVCB). Means and standard deviations (SDs) for each shift and rotation were calculated for each patient and for each IGRT modality. The Student's t tests and F-tests were performed to analyze the differences in the means and SDs. Necessary CTV-to-PTV margins were estimated. The repositioning shifts and day-to-day variations were large and generally similar for the 6 imaging modalities. Of the 2 most commonly used modalities, MVCT and KVorth, there were no statistically significant differences in the shifts and rotations (P = .15 and .59 for the RL and SI shifts, respectively; and P = .22 for rotation), except for shifts in AP direction (P = .002). The estimated CTV-to-PTV margins in the RL, SI, and AP directions would be 13.0, 10.4, and 11.7 mm from MVCT data, respectively, and 13.1, 8.6, and 10.8 mm from KVorth data, respectively, indicating that margins substantially larger than 5 mm used with daily IGRT would be required in the absence of IGRT. The observed large daily repositioning errors and the large variations among institutions imply that daily IGRT is necessary for this tumor site, particularly in multi-institutional trials. Otherwise, a CTV-to-PTV margin of 1.5 cm is required to account for daily setup variations. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Meloplication of the malar fat pads by percutaneous cable-suture technique for midface rejuvenation: outcome study (392 cases, 6 years' experience).

PubMed

Sasaki, Gordon H; Cohen, Andrew T

2002-08-01

The aging anterior midface is restored by reversing the contour undulations produced by sagging of the malar fat pad complex toward the nasolabial line. The convex irregularities include the exposed bulges of the post-septal fat, the unveiled malar bag, and the prominent nasolabial fold. The depressed irregularities are represented by the cresent-shaped hollow at the lid-cheek junction, the accentuated nasojugal groove, and the deepening nasolabial line. Repositioning of the ptotic malar fat pad, among other elements of meloplasty, represents a key procedure. In this study, the malar fat pad has been defined as a fan-shaped structure by external anatomic landmarks that correlate closely to the findings in cadaveric dissections and clinical cases, confirmed by the findings of spiral computed tomographic scanning. A simple but powerful adjustable and long-lasting percutaneous suture elevation technique was developed over the past 6 years by the senior author (G.H.S.) to reposition the fat pad in a superolateral direction. Through a dot incision within the nasolabial line, a permanent CV-3 Gore-Tex (or 4-0 clear Prolene) suspension suture, looped through a Gore-Tex anchor graft, suspends the malar fat pad in a direction perpendicular to the nasolabial line. A second suspension system is identically passed through another lower dot incision to broaden the repositioning vectors on the malar fat pad. Tension on each of the paired suture ends elevates the malar fat pad by 1 to 3 mm as measured from the nasolabial dot incisions. The sutures are fixed to the deep temporal fascia through a Gore-Tex tab, effectively stabilizing the soft-tissue repositioning. This maneuver may be performed in younger patients who present with an isolated malar fat pad ptosis without excess facial skin. The procedure may also be incorporated into open rhytidectomies to address this recalcitrant area along with superficial musculoaponeurotic system tightening. A total of 392 patients since 1995 underwent suture elevation of the malar fat pads. An outcome study indicated that the usage of two permanent sutures with Gore-Tex anchor grafts since 1998 resulted in improvement in midface rejuvenation of over 82 percent. Early and late complication rates were small and temporary. Patient acceptance was excellent, indicative of the benefits of anatomic repositioning of the malar fat pad complex.

Hot spot analysis for driving the development of hits into leads in fragment based drug discovery

PubMed Central

Hall, David R.; Ngan, Chi Ho; Zerbe, Brandon S.; Kozakov, Dima; Vajda, Sandor

2011-01-01

Fragment based drug design (FBDD) starts with finding fragment-sized compounds that are highly ligand efficient and can serve as a core moiety for developing high affinity leads. Although the core-bound structure of a protein facilitates the construction of leads, effective design is far from straightforward. We show that protein mapping, a computational method developed to find binding hot spots and implemented as the FTMap server, provides information that complements the fragment screening results and can drive the evolution of core fragments into larger leads with a minimal loss or, in some cases, even a gain in ligand efficiency. The method places small molecular probes, the size of organic solvents, on a dense grid around the protein, and identifies the hot spots as consensus clusters formed by clusters of several probes. The hot spots are ranked based on the number of probe clusters, which predicts the binding propensity of the subsites and hence their importance for drug design. Accordingly, with a single exception the main hot spot identified by FTMap binds the core compound found by fragment screening. The most useful information is provided by the neighboring secondary hot spots, indicating the regions where the core can be extended to increase its affinity. To quantify this information, we calculate the density of probes from mapping, which describes the binding propensity at each point, and show that the change in the correlation between a ligand position and the probe density upon extending or repositioning the core moiety predicts the expected change in ligand efficiency. PMID:22145575

Investigational drugs in early development for treating dengue infection.

PubMed

Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

2016-09-01

Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development. This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization's International Clinical Trials Registry Platform web portal using the search term 'dengue' on December 31(st), 2015. None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict 'high-risk' patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.

Can electromagnetic-navigated maxillary positioning replace occlusional splints in orthognathic surgery? A clinical pilot study.

PubMed

Berger, Moritz; Nova, Igor; Kallus, Sebastian; Ristow, Oliver; Freudlsperger, Christian; Eisenmann, Urs; Dickhaus, Hartmut; Engel, Michael; Hoffmann, Jürgen; Seeberger, Robin

2017-10-01

Because of the inaccuracy of intermaxillary splints in orthognathic surgery, intraoperative guidance via a real time navigation system might represent a suitable method for enhancing the precision of maxillary positioning. Therefore, in this clinical trial, maxillary repositioning after Le Fort I osteotomy was guided splintless by an electromagnetic navigation system. Conservatively planned maxillary reposition in each of 5 patients was transferred to a novel software module of the electromagnetic navigation system. Intraoperatively, after Le Fort I osteotomy, the software guided the maxilla to the targeted position. Accuracy was evaluated by pre- and postoperative cone beam computer tomography imaging (the vectorial distance of the incisal marker points was measured in three dimensions) and compared with that of a splint transposed control group. The repositioning of the maxilla guided by the electromagnetic navigation system was intuitive and simple to accomplish. The achieved maxillary position with a deviation of 0.7 mm on average to the planned position was equally accurate compared with that of the splint transposed control group of 0.5 mm (p > 0.05). The data of this clinical study display good accuracy for splintless electromagnetic-navigated maxillary positioning. Nevertheless, this method does not surpass the splint-encoded gold standard with regard to accuracy. Future investigations will be necessary to show the full potential of electromagnetic navigation in orthognathic surgery. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

TEAM-UP for quality: a cluster randomized controlled trial protocol focused on preventing pressure ulcers through repositioning frequency and precipitating factors.

PubMed

Yap, Tracey L; Kennerly, Susan M; Horn, Susan D; Bergstrom, Nancy; Datta, Santanu; Colon-Emeric, Cathleen

2018-02-20

Pressure ulcers/injuries (PrUs), a critical concern for nursing homes (NH), are responsible for chronic wounds, amputations, septic infections, and premature deaths. PrUs occur most commonly in older adults and NH residence is a risk factor for their development, with at least one of every nine U.S. NH residents experiencing a PrU and many NHs having high incidence and prevalence rates, in some instances well over 20%. PrU direct treatment costs are greater than prevention costs, making prevention-focused protocols critical. Current PrU prevention protocols recommend repositioning residents at moderate, high, and severe risk every 2 h. The advent of visco-elastic (VE) high-density foam support-surfaces over the past decade may now make it possible to extend the repositioning interval to every 3 or 4 h without increasing PrU development. The TEAM-UP (Turn Everyone And Move for Ulcer Prevention) study aims to determine: 1) whether repositioning interval can be extended for NH residents without compromising PrU incidence and 2) how changes in medical severity interact with changes in risk level and repositioning schedule to predict PrU development. In this proposed cluster randomized study, 9 NHs will be randomly assigned to one of three repositioning intervals (2, 3, or 4 h) for a 4-week period. Each enrolled site will use a single NH-wide repositioning interval as the standard of care for residents at low, moderate, and high risk of PrU development (N = 951) meeting the following criteria: minimum 3-day stay, without PrUs, no adhesive allergy, and using VE support surfaces (mattresses). An FDA-cleared patient monitoring system that records position/movement of these residents via individual wireless sensors will be used to visually cue staff when residents need repositioning and document compliance with repositioning protocols. This study will advance knowledge about repositioning frequency and clinically assessed PrU risk level in relation to PrU incidence and medical severity. Outcomes of this research will contribute to future guidelines for more precise preventive nursing practices and refinement of PrU prevention guidelines. Clinical Trial Registration: NCT02996331 .

Probabilistic drug connectivity mapping

PubMed Central

2014-01-01

Background The aim of connectivity mapping is to match drugs using drug-treatment gene expression profiles from multiple cell lines. This can be viewed as an information retrieval task, with the goal of finding the most relevant profiles for a given query drug. We infer the relevance for retrieval by data-driven probabilistic modeling of the drug responses, resulting in probabilistic connectivity mapping, and further consider the available cell lines as different data sources. We use a special type of probabilistic model to separate what is shared and specific between the sources, in contrast to earlier connectivity mapping methods that have intentionally aggregated all available data, neglecting information about the differences between the cell lines. Results We show that the probabilistic multi-source connectivity mapping method is superior to alternatives in finding functionally and chemically similar drugs from the Connectivity Map data set. We also demonstrate that an extension of the method is capable of retrieving combinations of drugs that match different relevant parts of the query drug response profile. Conclusions The probabilistic modeling-based connectivity mapping method provides a promising alternative to earlier methods. Principled integration of data from different cell lines helps to identify relevant responses for specific drug repositioning applications. PMID:24742351

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

PubMed

Boyer, Arnaud; Pasquier, Eddy; Tomasini, Pascale; Ciccolini, Joseph; Greillier, Laurent; Andre, Nicolas; Barlesi, Fabrice; Mascaux, Celine

2018-03-31

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro , half have been evaluated in vivo in animal models of MPM and only three ( i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials. Copyright ©ERS 2018.

Current Care and Investigational Therapies in Achondroplasia.

PubMed

Unger, Sheila; Bonafé, Luisa; Gouze, Elvire

2017-04-01

The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications.

Repositioning Of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.

PubMed

Marcuzzi, Annalisa; Loganes, Claudia; Celeghini, Claudio; Kleiner, Giulio

2017-09-11

Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase (MK), due to a mutation in the MVK gene, leads to the shortage of mevalonate-derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-1 (IL-1) can significantly reduce inflammation, they cannot completely control the clinical symptoms that affects the nervous system. For this reason, MKD can still be considered an orphan drug disease. Cellular models for MKD can be obtained by biochemical inhibition of mevalonate-derived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase (SQS) able to increase the availability of isoprenoids intermediates upstream the enzymatic block. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Epigenetics, drugs of abuse, and the retroviral promoter

PubMed Central

Shirazi, Jasmine; Shah, Sonia; Sagar, Divya; Nonnemacher, Michael R.; Wigdahl, Brian; Khan, Zafar K.; Jain, Pooja

2013-01-01

Drug abuse alone has been shown to cause epigenetic changes in brain tissue that have been shown to play roles in addictive behaviors. In conjunction with HIV-1 infection, it can cause epigenetic changes at the viral promoter that can result in altered gene expression, and exacerbate disease progression overall. This review entails an in-depth look at research conducted on the epigenetic effects of three of the most widely abused drugs (cannabinoids, opioids, and cocaine), with a particular focus on the mechanisms through which these drugs interact with HIV-1 infection at the viral promoter. Here we discuss the impact of this interplay on disease progression from the point of view of the nature of gene regulation at the level of chromatin accessibility, chromatin remodeling, and nucleosome repositioning. Given the importance of chromatin remodeling and DNA methylation in controlling the retroviral promoter, and the high susceptibility of the drug abusing population of individuals to HIV infection, it would be beneficial to understand the way in which the host genome is modified and regulated by drugs of abuse. PMID:24218017

Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique.

PubMed

Hao, Ming; Wang, Yanli; Bryant, Stephen H

2016-02-25

Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision-recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. Published by Elsevier B.V.

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing.

PubMed

Soave, Claire L; Guerin, Tracey; Liu, Jinbao; Dou, Q Ping

2017-12-01

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

AORN ergonomic tool 2: positioning and repositioning the supine patient on the OR bed.

PubMed

Waters, Thomas; Short, Manon; Lloyd, John; Baptiste, Andrea; Butler, Lorraine; Petersen, Carol; Nelson, Audrey

2011-04-01

Positioning or repositioning a patient on the OR bed in preparation for a surgical procedure presents a high risk for musculoskeletal disorders, such as low-back and shoulder injuries, for perioperative personnel. Safe patient handling requires knowledge of current ergonomic safety concepts, scientific evidence, and equipment and devices to ensure that neither the patient nor the caregiver is at risk for injury. AORN Ergonomic Tool 2: Positioning and Repositioning the Supine Patient on the OR Bed provides guidelines that enable perioperative personnel to determine safe methods for positioning and repositioning a patient in the semi-Fowler, lateral, or lithotomy position in preparation for surgery. Published by Elsevier Inc.

Long-term corneal endothelial cell changes in pediatric intraocular lens reposition and exchange cases.

PubMed

Wang, Yan; Wu, Mingxing; Zhu, Liyuan; Liu, Yizhi

2012-04-01

To evaluate long-term corneal endothelial cell changes of intraocular lens (IOL) reposition and exchange in children. State key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China In this retrospective study, all IOL reposition and exchange procedures performed in patients under 14 years old between January 1999 and April 2009 were included. Follow-up outcomes included corneal endothelial cell density, hexagonality, coefficient of variance, average cell size. IOL reposition procedures in 12 eyes (12 cases) (reposition group, RPG), and IOL exchanges in eight eyes (eight cases) (exchange group, EXG) were performed because of IOL pupillary capture or IOL dislocation. Median of follow-up was 44.5 months in RPG and 66.2 months in EXG. The density of corneal endothelial cells in RPG (2,053 ± 493/mm(2)) and EXG (2,100 ± 758/mm(2)) was significantly decreased in comparison to the control eyes (3,116 ± 335/mm(2)). Hexagonality of corneal endothelial cells and coefficient of variance showed no difference among the control group, RPG and EXG (P > 0.05). The density of corneal endothelial cells was conspicuously decreased after IOL reposition or exchange procedures in childhood cases. Longer follow-up must be conducted in these cases.

Sequencing of bimaxillary surgery in the correction of vertical maxillary excess: retrospective study.

PubMed

Salmen, F S; de Oliveira, T F M; Gabrielli, M A C; Pereira Filho, V A; Real Gabrielli, M F

2018-06-01

The aim of this study was to evaluate the precision of bimaxillary surgery performed to correct vertical maxillary excess, when the procedure is sequenced with mandibular surgery first or maxillary surgery first. Thirty-two patients, divided into two groups, were included in this retrospective study. Group 1 comprised patients who received bimaxillary surgery following the classical sequence with repositioning of the maxilla first. Patients in group 2 received bimaxillary surgery, but the mandible was operated on first. The precision of the maxillomandibular repositioning was determined by comparison of the digital prediction and postoperative tracings superimposed on the cranial base. The data were tabulated and analyzed statistically. In this sample, both surgical sequences provided adequate clinical accuracy. The classical sequence, repositioning the maxilla first, resulted in greater accuracy for A-point and the upper incisor edge vertical position. Repositioning the mandible first allowed greater precision in the vertical position of pogonion. In conclusion, although both surgical sequences may be used, repositioning the mandible first will result in greater imprecision in relation to the predictive tracing than repositioning the maxilla first. The classical sequence resulted in greater accuracy in the vertical position of the maxilla, which is key for aesthetics. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Effect of warning placement on the information processing of college students reading an OTC drug facts panel.

PubMed

Bhansali, Archita H; Sangani, Darshan S; Mhatre, Shivani K; Sansgiry, Sujit S

2018-01-01

To compare three over-the-counter (OTC) Drug Facts panel versions for information processing optimization among college students. University of Houston students (N = 210) participated in a cross-sectional survey from January to May 2010. A current FDA label was compared to two experimental labels developed using the theory of CHREST to test information processing by re-positioning the warning information within the Drug Facts panel. Congruency was defined as placing like information together. Information processing was evaluated using the OTC medication Label Evaluation Process Model (LEPM): label comprehension, ease-of-use, attitude toward the product, product evaluation, and purchase intention. Experimental label with chunked congruent information (uses-directions-other information-warnings) was rated significantly higher than the current FDA label and had the best average scores among the LEPM information processing variables. If replications uphold these findings, the FDA label design might be revised to improve information processing.

Autonomous bone reposition around anatomical landmark for robot-assisted orthognathic surgery.

PubMed

Woo, Sang-Yoon; Lee, Sang-Jeong; Yoo, Ji-Yong; Han, Jung-Joon; Hwang, Soon-Jung; Huh, Kyung-Hoe; Lee, Sam-Sun; Heo, Min-Suk; Choi, Soon-Chul; Yi, Won-Jin

2017-12-01

The purpose of this study was to develop a new method for enabling a robot to assist a surgeon in repositioning a bone segment to accurately transfer a preoperative virtual plan into the intraoperative phase in orthognathic surgery. We developed a robot system consisting of an arm with six degrees of freedom, a robot motion-controller, and a PC. An end-effector at the end of the robot arm transferred the movements of the robot arm to the patient's jawbone. The registration between the robot and CT image spaces was performed completely preoperatively, and the intraoperative registration could be finished using only position changes of the tracking tools at the robot end-effector and the patient's splint. The phantom's maxillomandibular complex (MMC) connected to the robot's end-effector was repositioned autonomously by the robot movements around an anatomical landmark of interest based on the tool center point (TCP) principle. The robot repositioned the MMC around the TCP of the incisor of the maxilla and the pogonion of the mandible following plans for real orthognathic patients. The accuracy of the robot's repositioning increased when an anatomical landmark for the TCP was close to the registration fiducials. In spite of this influence, we could increase the repositioning accuracy at the landmark by using the landmark itself as the TCP. With its ability to incorporate virtual planning using a CT image and autonomously execute the plan around an anatomical landmark of interest, the robot could help surgeons reposition bones more accurately and dexterously. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Nanotechnology as a potential therapeutic alternative for schistosomiasis.

PubMed

Tomiotto-Pellissier, Fernanda; Miranda-Sapla, Milena Menegazzo; Machado, Laís Fernanda; Bortoleti, Bruna Taciane da Silva; Sahd, Claudia Stoeglehner; Chagas, Alan Ferreira; Assolini, João Paulo; Oliveira, Francisco José de Abreu; Pavanelli, Wander Rogério; Conchon-Costa, Ivete; Costa, Idessania Nazareth; Melanda, Francine Nesello

2017-10-01

Schistosomiasis is a neglected disease that affects millions of people worldwide, recognized as the most important human helminth infection in terms of morbidity and mortality. The treatment of choice presents low bioavailability and water solubility, in addition to the induction of parasite resistance. In this context, researchers have been conducting studies seeking to develop new drugs to ensure safety, quality, and efficacy against this parasitosis. In this scenario, nanotechnology arises including the drug delivery systems in nanoscale: nanoemulsions, liposomes and nanoparticles. These drug delivery systems have been extensively applied for in vitro and in vivo studies against Schistosoma spp. with promising results. This review pointed out the most relevant development scenarios regarding the treatment of schistosomiasis as well as the application of nanotechnology as a vaccine, highlighting the use of nanotechnology as an alternative therapy for both the repositioning of drugs and the use of new pharmaceutical products, with promising results regarding the aforementioned disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Repositioning Proton Pump Inhibitors as Anticancer Drugs by Targeting the Thioesterase Domain of Human Fatty Acid Synthase

PubMed Central

2015-01-01

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells. PMID:25513712

Timing of PMMA cement application for pedicle screw augmentation affects screw anchorage.

PubMed

Schmoelz, Werner; Heinrichs, Christian Heinz; Schmidt, Sven; Piñera, Angel R; Tome-Bermejo, Felix; Duart, Javier M; Bauer, Marlies; Galovich, Luis Álvarez

2017-11-01

Cement augmentation is an established method to increase the pedicle screw (PS) anchorage in osteoporotic vertebral bodies. The ideal timing for augmentation when a reposition maneuver is necessary is controversial. While augmentation of the PS before reposition maneuver may increase the force applied it on the vertebrae, it bears the risk to impair PS anchorage, whereas augmenting the PS after the maneuver may restore this anchorage and prevent early screw loosening. The purpose of the present study was to evaluate the effect of cement application timing on PS anchorage in the osteoporotic vertebral body. Ten lumbar vertebrae (L1-L5) were used for testing. The left and right pedicles of each vertebra were instrumented with the same PS size and used for pairwise comparison of the two timing points for augmentation. For the reposition maneuver, the left PS was loaded axially under displacement control (2 × ±2 mm, 3 × ±6 mm, 3 × ±10 mm) to simulate a reposition maneuver. Subsequently, both PS were augmented with 2 ml PMMA cement. The same force as measured during the left PS maneuver was applied to the previously augmented right hand side PS [2 × F (±2 mm), 3 × F (±6 mm), 3 × F (±10 mm)]. Both PS were cyclically loaded with initial forces of +50 and -50 N, while the lower force was increased by 5 N every 100 cycles until total failure of the PS. The PS motion was measured with a 3D motion analysis system. After cyclic loading stress, X-rays were taken to identify the PS loosening mechanism. In comparison with PS augmented prior to the reposition maneuver, PS augmented after the reposition maneuver showed a significant higher number of load cycles until failure (5930 ± 1899 vs 3830 ± 1706, p = 0.015). The predominant loosening mechanism for PS augmented after the reposition maneuver was PS toggling with the attached cement cloud within the trabecular bone. While PS augmented prior to the reposition, maneuver showed a motion of the screw within the cement cloud. The time of cement application has an effect on PS anchorage in the osteoporotic vertebral body if a reposition maneuver of the instrumented vertebrae is carried out. PS augmented after the reposition maneuver showed a significant higher number of load cycles until screw loosening.

Impact of PET/CT system, reconstruction protocol, data analysis method, and repositioning on PET/CT precision: An experimental evaluation using an oncology and brain phantom.

PubMed

Mansor, Syahir; Pfaehler, Elisabeth; Heijtel, Dennis; Lodge, Martin A; Boellaard, Ronald; Yaqub, Maqsood

2017-12-01

In longitudinal oncological and brain PET/CT studies, it is important to understand the repeatability of quantitative PET metrics in order to assess change in tracer uptake. The present studies were performed in order to assess precision as function of PET/CT system, reconstruction protocol, analysis method, scan duration (or image noise), and repositioning in the field of view. Multiple (repeated) scans have been performed using a NEMA image quality (IQ) phantom and a 3D Hoffman brain phantom filled with 18 F solutions on two systems. Studies were performed with and without randomly (< 2 cm) repositioning the phantom and all scans (12 replicates for IQ phantom and 10 replicates for Hoffman brain phantom) were performed at equal count statistics. For the NEMA IQ phantom, we studied the recovery coefficients (RC) of the maximum (SUV max ), peak (SUV peak ), and mean (SUV mean ) uptake in each sphere as a function of experimental conditions (noise level, reconstruction settings, and phantom repositioning). For the 3D Hoffman phantom, the mean activity concentration was determined within several volumes of interest and activity recovery and its precision was studied as function of experimental conditions. The impact of phantom repositioning on RC precision was mainly seen on the Philips Ingenuity PET/CT, especially in the case of smaller spheres (< 17 mm diameter, P < 0.05). This effect was much smaller for the Siemens Biograph system. When exploring SUV max , SUV peak , or SUV mean of the spheres in the NEMA IQ phantom, it was observed that precision depended on phantom repositioning, reconstruction algorithm, and scan duration, with SUV max being most and SUV peak least sensitive to phantom repositioning. For the brain phantom, regional averaged SUVs were only minimally affected by phantom repositioning (< 2 cm). The precision of quantitative PET metrics depends on the combination of reconstruction protocol, data analysis methods and scan duration (scan statistics). Moreover, precision was also affected by phantom repositioning but its impact depended on the data analysis method in combination with the reconstructed voxel size (tissue fraction effect). This study suggests that for oncological PET studies the use of SUV peak may be preferred over SUV max because SUV peak is less sensitive to patient repositioning/tumor sampling. © 2017 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

[Development of a novel liquid injection system].

PubMed

Chen, Kai; Lv, Yong-Gui

2009-11-01

A liquid jet injector employs compressed gas or spring to produce a high-velocity stream to deliver liquid drug into human body through skin. There are many clinical jet injection products available, none of which is domestic. A new liquid jet injector is designed based on a comprehensive analysis of the current products. The injector consists of an ejector, trigger and a re-positioning mechanism. The jets characteristics of sample injector are tested, and the results show that the maximum exit pressure is above 15 MPa, a threshold value for penetrating into the skin.

Monorail system for percutaneous repositioning of the Greenfield vena caval filter.

PubMed

Guthaner, D F; Wyatt, J O; Mehigan, J T; Wright, A M; Breen, J F; Wexler, L

1990-09-01

The authors describe a technique for removing or repositioning a malpositioned Greenfield inferior vena caval filter. A "monorail" system was used, in which a wire was passed from the femoral vein through the apical hole in the filter and out the internal jugular vein; the wire was held taut from above and below and thus facilitated repositioning or removal of the filter. The technique was used successfully in two cases.

Effects on G Tolerance While Biting Down on a Mandibular Orthopedic Repositioning Appliance (MORA) Levels.

DTIC Science & Technology

1990-10-01

Repositioning Appliance (MORA) that properly aligns the temporo mandibular joint (TMJ) requires voluntary contraction of the masseter and temporal’s...growth, malocclusion, or bad oral posture may cause the Temporo Mandibular Joint (TMJ) to grad- ually become misaligned. The masseter and other muscles...books have been published on the use of a Mandibular Orthopedic Repositioning Appliance (MORA) to realign the joint (Figure 1). Realignment is claimed

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

PubMed

de Jong, Simone; Vidler, Lewis R; Mokrab, Younes; Collier, David A; Breen, Gerome

2016-08-01

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy. © The Author(s) 2016.

Repurposing drugs for glioblastoma: From bench to bedside.

PubMed

Basso, João; Miranda, Ana; Sousa, João; Pais, Alberto; Vitorino, Carla

2018-08-01

Glioblastoma multiforme is the most common, aggressive and lethal type of brain tumor. It is a stage IV cancer disease with a poor prognosis, as the current therapeutic options (surgery, radiotherapy and chemotherapy) are not able to eradicate tumor cells. The approach to treat glioblastoma has not suffered major changes over the last decade and temozolomide (TMZ) remains the mainstay for chemotherapy. However, resistance mechanisms to TMZ and other chemotherapeutic agents are becoming more frequent. The lack of effective options is a reality that may be counterbalanced by repositioning known and commonly used drugs for other diseases. This approach takes into consideration the available pharmacokinetic, pharmacodynamic, toxicity and safety data, and allows a much faster and less expensive drug and product development process. In this review, an extensive literature search is conducted aiming to list drugs with repurposing usage, based on their preferential damage in glioblastoma cells through various mechanisms. Some of these drugs have already entered clinical trials, exhibiting favorable outcomes, which sparks their potential application in glioblastoma treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays

PubMed Central

Oliver, Sarah; Willard, Francis S.; Heidler, Steven; Peery, Robert B.; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S.; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P.; Simeonov, Anton; Sittampalam, G. Sitta; Husain, Saba; Franklin, Natalie; Wild, David J.; Yang, Jeremy J.; Sutherland, Jeffrey J.; Thomas, Craig J.

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben. PMID:26177200

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

PubMed

Lee, Jonathan A; Shinn, Paul; Jaken, Susan; Oliver, Sarah; Willard, Francis S; Heidler, Steven; Peery, Robert B; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P; Simeonov, Anton; Sittampalam, G Sitta; Husain, Saba; Franklin, Natalie; Wild, David J; Yang, Jeremy J; Sutherland, Jeffrey J; Thomas, Craig J

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

Cervicocephalic kinesthetic sensibility in young and middle-aged adults with or without a history of mild neck pain.

PubMed

Teng, C-C; Chai, H; Lai, D-M; Wang, S-F

2007-02-01

Previous research has shown that there is no significant relationship between the degree of structural degeneration of the cervical spine and neck pain. We therefore sought to investigate the potential role of sensory dysfunction in chronic neck pain. Cervicocephalic kinesthetic sensibility, expressed by how accurately an individual can reposition the head, was studied in three groups of individuals, a control group of 20 asymptomatic young adults and two groups of middle-aged adults (20 subjects in each group) with or without a history of mild neck pain. An ultrasound-based three-dimensional coordinate measuring system was used to measure the position of the head and to test the accuracy of repositioning. Constant error (indicating that the subject overshot or undershot the intended position) and root mean square errors (representing total errors of accuracy and variability) were measured during repositioning of the head to the neutral head position (Head-to-NHP) and repositioning of the head to the target (Head-to-Target) in three cardinal planes (sagittal, transverse, and frontal). Analysis of covariance (ANCOVA) was used to test the group effect, with age used as a covariate. The constant errors during repositioning from a flexed position and from an extended position to the NHP were significantly greater in the middle-aged subjects than in the control group (beta=0.30 and beta=0.60, respectively; P<0.05 for both). In addition, the root mean square errors during repositioning from a flexed or extended position to the NHP were greater in the middle-aged subjects than in the control group (beta=0.27 and beta=0.49, respectively; P<0.05 for both). The root mean square errors also increased during Head-to-Target in left rotation (beta=0.24;P<0.05), but there was no difference in the constant errors or root mean square errors during Head-to-NHP repositioning from other target positions (P>0.05). The results indicate that, after controlling for age as a covariate, there was no group effect. Thus, age appears to have a profound effect on an individual's ability to accurately reposition the head toward the neutral position in the sagittal plane and repositioning the head toward left rotation. A history of mild chronic neck pain alone had no significant effect on cervicocephalic kinesthetic sensibility.

Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems

PubMed Central

Herrando-Grabulosa, Mireia; Mulet, Roger; Pujol, Albert; Mas, José Manuel; Navarro, Xavier; Aloy, Patrick; Coma, Mireia; Casas, Caty

2016-01-01

Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis. PMID:26807587

Minimal invasive right ventricular and atrial pacemaker lead repositioning as a first alternative is superior in avoiding pocket complications with passive fixation leads.

PubMed

Osztheimer, István; Szilágyi, Szabolcs; Pongor, Zsuzsanna; Zima, Endre; Molnár, Levente; Tahin, Tamás; Özcan, Emin Evren; Széplaki, Gábor; Merkely, Béla; Gellér, László

2017-06-01

Lead dislocations of pacemaker systems are reported in all and even in high-volume centers. Repeated procedures necessitated by lead dislocations are associated with an increased risk of complications. We investigated a minimal invasive method for right atrial and ventricular lead repositioning. The minimal invasive method was applied only when passive fixation leads were implanted. During the minimal invasive procedure, a steerable catheter was advanced through the femoral vein to move the distal end of the lead to the appropriate position. Retrospective data collection was conducted in all patients with minimal invasive and with conventional method, at a single center between September 2006 and December 2012. Forty-five minimal invasive lead repositionings were performed, of which eight were acutely unsuccessful and nine electrodes re-dislocated after the procedure. One hundred two leads were repositioned with opening of the pocket during the same time, including the ones with unsuccessful minimal invasive repositionings. One procedure was acutely unsuccessful in this group and four re-dislocations happened. A significant difference of success rates was noted (66.6% vs. 95.1%, p = 0.001). One complication was observed during the minimal invasive lead repositionings (left ventricular lead microdislodgement). Open-pocket procedures showed different types of complications (pneumothorax, subclavian artery puncture, pericardial effusion, hematoma, fever, device-associated infection which necessitated explantation, atrial lead dislodgement while repositioning the ventricular one, deterioration of renal function). The minimal invasive method as a first alternative is safe and feasible. In those cases when it cannot be carried out successfully, the conventional method is applicable.

Percutaneous transfemoral repositioning of malpositioned central venous catheters.

PubMed

Hartnell, G G; Roizental, M

1995-04-01

Central venous catheters inserted by blind surgical placement may not advance into a satisfactory position and may require repositioning. Malpositioning via surgical insertion is common in patients in whom central venous catheters have previously been placed, as these patients are more likely to have central venous thrombosis and distortion of central venous anatomy. This is less of a problem when catheter placement is guided by imaging; however, even when insertion is satisfactory, central venous catheters may become displaced spontaneously after insertion (Fig. 1). Repositioning can be effected by direct manipulation using guidewires or tip-deflecting wires [1, 2], by manipulation via a transfemoral venous approach [3-5], and by injection of contrast material or saline [6]. Limitations of the direct approach include (1) the number and type of maneuvers that can be performed to effect repositioning when anatomy is distorted, (2) difficulty in accessing the catheter, and (3) the risk of introducing infection. Moreover, these patients are often immunosuppressed, and there is a risk of introducing infection by exposing and directly manipulating the venous catheter. Vigorous injection of contrast material or saline may be unsuccessful for the same reasons: It seldom exerts sufficient force to reposition large-caliber central venous catheters and may cause vessel damage or rupture if injection is made into a small or thrombosed vessel. We illustrate several alternative methods for catheter repositioning via a transfemoral venous approach.

Tongue-lip adhesion and tongue repositioning for obstructive sleep apnoea in Pierre Robin sequence: A systematic review and meta-analysis.

PubMed

Camacho, M; Noller, M W; Zaghi, S; Reckley, L K; Fernandez-Salvador, C; Ho, E; Dunn, B; Chan, D K

2017-05-01

To search for studies on tongue-lip adhesion and tongue repositioning used as isolated treatments for obstructive sleep apnoea in children with Pierre Robin sequence. A systematic literature search of PubMed/Medline and three additional databases, from inception through to 8 July 2016, was performed by two authors. Seven studies with 90 patients (59 tongue-lip adhesion and 31 tongue repositioning patients) met the inclusion criteria. Tongue-lip adhesion reduced the mean (± standard deviation) apnoea/hypopnoea index from 30.8 ± 22.3 to 15.4 ± 18.9 events per hour (50 per cent reduction). The apnoea/hypopnoea index mean difference for tongue-lip adhesion was -15.28 events per hour (95 per cent confidence interval = -30.70 to 0.15; p = 0.05). Tongue-lip adhesion improved the lowest oxygen saturation from 75.8 ± 6.8 to 84.4 ± 7.3 per cent. Tongue repositioning reduced the apnoea/hypopnoea index from 46.5 to 17.4 events per hour (62.6 per cent reduction). Tongue repositioning improved the mean oxygen saturation from 90.8 ± 1.2 to 95.0 ± 0.5 per cent. Tongue-lip adhesion and tongue repositioning can improve apnoea/hypopnoea index and oxygenation parameters in children with Pierre Robin sequence and obstructive sleep apnoea.

System for routine surface anthropometry using reprojection registration

NASA Astrophysics Data System (ADS)

Sadleir, R. J.; Owens, R. A.; Hartmann, P. E.

2003-11-01

Range data measurement can be usefully applied to non-invasive monitoring of anthropometric changes due to disease, healing or during normal physiological processes. We have developed a computer vision system that allows routine capture of biological surface shapes and accurate measurement of anthropometric changes, using a structured light stripe triangulation system. In many applications involving relocation of soft tissue for image-guided surgery or anthropometry it is neither accurate nor practical to apply fiducial markers directly to the body. This system features a novel method of achieving subject re-registration that involves application of fiducials by a standard data projector. Calibration of this reprojector is achieved using a variation of structured lighting techniques. The method allows accurate and comparable repositioning of elastic surfaces. Tests of repositioning using the reprojector found a significant improvement in subject registration compared to an earlier method which used video overlay comparison only. It has a current application to the measurement of breast volume changes in lactating mothers, but may be extended to any application where repeatable positioning and measurement is required.

Medical Marijuana in the Workplace

PubMed Central

Targino, Marcelo C.; Fanciullo, Gilbert J.; Martin, Douglas W.; Hartenbaum, Natalie P.; White, Jeremy M.; Franklin, Phillip

2015-01-01

Although possession and use of marijuana is prohibited by federal law, legalization in four states (Alaska, Colorado, Oregon, and Washington) and allowance for palliation and therapy in 19 others may reposition the drug away from the fringes of society. This evolving legal environment, and growing scientific evidence of its effectiveness for select health conditions, requires assessment of the safety and appropriateness of marijuana within the American workforce. Although studies have suggested that marijuana may be used with reasonable safety in some controlled environments, there are potential consequences to its use that necessitate employer scrutiny and concern. Several drug characteristics must be considered, including Δ9-tetrahydrocannabinol (Δ9-THC, or THC) concentration, route of administration, dose and frequency, and pharmacokinetics, as well as the risks inherent to particular workplace environments. PMID:25951421

Giving Drugs a Second Chance: Overcoming Regulatory and Financial Hurdles in Repurposing Approved Drugs As Cancer Therapeutics

PubMed Central

Hernandez, J. Javier; Pryszlak, Michael; Smith, Lindsay; Yanchus, Connor; Kurji, Naheed; Shahani, Vijay M.; Molinski, Steven V.

2017-01-01

The repositioning or “repurposing” of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these “new” medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike. PMID:29184849

Giving Drugs a Second Chance: Overcoming Regulatory and Financial Hurdles in Repurposing Approved Drugs As Cancer Therapeutics.

PubMed

Hernandez, J Javier; Pryszlak, Michael; Smith, Lindsay; Yanchus, Connor; Kurji, Naheed; Shahani, Vijay M; Molinski, Steven V

2017-01-01

The repositioning or "repurposing" of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these "new" medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike.

Virtual skeletal complex model- and landmark-guided orthognathic surgery system.

PubMed

Lee, Sang-Jeong; Woo, Sang-Yoon; Huh, Kyung-Hoe; Lee, Sam-Sun; Heo, Min-Suk; Choi, Soon-Chul; Han, Jeong Joon; Yang, Hoon Joo; Hwang, Soon Jung; Yi, Won-Jin

2016-05-01

In this study, correction of the maxillofacial deformities was performed by repositioning bone segments to an appropriate location according to the preoperative planning in orthognathic surgery. The surgery was planned using the patient's virtual skeletal models fused with optically scanned three-dimensional dentition. The virtual maxillomandibular complex (MMC) model of the patient's final occlusal relationship was generated by fusion of the maxillary and mandibular models with scanned occlusion. The final position of the MMC was simulated preoperatively by planning and was used as a goal model for guidance. During surgery, the intraoperative registration was finished immediately using only software processing. For accurate repositioning, the intraoperative MMC model was visualized on the monitor with respect to the simulated MMC model, and the intraoperative positions of multiple landmarks were also visualized on the MMC surface model. The deviation errors between the intraoperative and the final positions of each landmark were visualized quantitatively. As a result, the surgeon could easily recognize the three-dimensional deviation of the intraoperative MMC state from the final goal model without manually applying a pointing tool, and could also quickly determine the amount and direction of further MMC movements needed to reach the goal position. The surgeon could also perform various osteotomies and remove bone interference conveniently, as the maxillary tracking tool could be separated from the MMC. The root mean square (RMS) difference between the preoperative planning and the intraoperative guidance was 1.16 ± 0.34 mm immediately after repositioning. After surgery, the RMS differences between the planning and the postoperative computed tomographic model were 1.31 ± 0.28 mm and 1.74 ± 0.73 mm for the maxillary and mandibular landmarks, respectively. Our method provides accurate and flexible guidance for bimaxillary orthognathic surgery based on intraoperative visualization and quantification of deviations for simulated postoperative MMC and landmarks. The guidance using simulated skeletal models and landmarks can complement and improve conventional navigational surgery for bone repositioning in the craniomaxillofacial area. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Canalith Repositioning Procedure

MedlinePlus

... repositioning procedure can help relieve benign paroxysmal positional vertigo (BPPV), a condition in which you have brief, ... dizziness that occur when you move your head. Vertigo usually comes from a problem with the part ...

Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer.

PubMed

Yeung, Tsz-Lun; Sheng, Jianting; Leung, Cecilia S; Li, Fuhai; Kim, Jaeyeon; Ho, Samuel Y; Matzuk, Martin M; Lu, Karen H; Wong, Stephen T C; Mok, Samuel C

2018-05-31

Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided. Activation of TGF-β-dependent and TGF-β-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04). Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer-stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.

Adaptive Liver Stereotactic Body Radiation Therapy: Automated Daily Plan Reoptimization Prevents Dose Delivery Degradation Caused by Anatomy Deformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leinders, Suzanne M.; Delft University of Technology, Delft; Breedveld, Sebastiaan

Purpose: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. Methods and Materials: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientationsmore » were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. Results: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. Conclusions: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.« less

A novel soft tissue prediction methodology for orthognathic surgery based on probabilistic finite element modelling

PubMed Central

Borghi, Alessandro; Ruggiero, Federica; Badiali, Giovanni; Bianchi, Alberto; Marchetti, Claudio; Rodriguez-Florez, Naiara; Breakey, Richard W. F.; Jeelani, Owase; Dunaway, David J.; Schievano, Silvia

2018-01-01

Repositioning of the maxilla in orthognathic surgery is carried out for functional and aesthetic purposes. Pre-surgical planning tools can predict 3D facial appearance by computing the response of the soft tissue to the changes to the underlying skeleton. The clinical use of commercial prediction software remains controversial, likely due to the deterministic nature of these computational predictions. A novel probabilistic finite element model (FEM) for the prediction of postoperative facial soft tissues is proposed in this paper. A probabilistic FEM was developed and validated on a cohort of eight patients who underwent maxillary repositioning and had pre- and postoperative cone beam computed tomography (CBCT) scans taken. Firstly, a variables correlation assessed various modelling parameters. Secondly, a design of experiments (DOE) provided a range of potential outcomes based on uniformly distributed input parameters, followed by an optimisation. Lastly, the second DOE iteration provided optimised predictions with a probability range. A range of 3D predictions was obtained using the probabilistic FEM and validated using reconstructed soft tissue surfaces from the postoperative CBCT data. The predictions in the nose and upper lip areas accurately include the true postoperative position, whereas the prediction under-estimates the position of the cheeks and lower lip. A probabilistic FEM has been developed and validated for the prediction of the facial appearance following orthognathic surgery. This method shows how inaccuracies in the modelling and uncertainties in executing surgical planning influence the soft tissue prediction and it provides a range of predictions including a minimum and maximum, which may be helpful for patients in understanding the impact of surgery on the face. PMID:29742139

A novel soft tissue prediction methodology for orthognathic surgery based on probabilistic finite element modelling.

PubMed

Knoops, Paul G M; Borghi, Alessandro; Ruggiero, Federica; Badiali, Giovanni; Bianchi, Alberto; Marchetti, Claudio; Rodriguez-Florez, Naiara; Breakey, Richard W F; Jeelani, Owase; Dunaway, David J; Schievano, Silvia

2018-01-01

Repositioning of the maxilla in orthognathic surgery is carried out for functional and aesthetic purposes. Pre-surgical planning tools can predict 3D facial appearance by computing the response of the soft tissue to the changes to the underlying skeleton. The clinical use of commercial prediction software remains controversial, likely due to the deterministic nature of these computational predictions. A novel probabilistic finite element model (FEM) for the prediction of postoperative facial soft tissues is proposed in this paper. A probabilistic FEM was developed and validated on a cohort of eight patients who underwent maxillary repositioning and had pre- and postoperative cone beam computed tomography (CBCT) scans taken. Firstly, a variables correlation assessed various modelling parameters. Secondly, a design of experiments (DOE) provided a range of potential outcomes based on uniformly distributed input parameters, followed by an optimisation. Lastly, the second DOE iteration provided optimised predictions with a probability range. A range of 3D predictions was obtained using the probabilistic FEM and validated using reconstructed soft tissue surfaces from the postoperative CBCT data. The predictions in the nose and upper lip areas accurately include the true postoperative position, whereas the prediction under-estimates the position of the cheeks and lower lip. A probabilistic FEM has been developed and validated for the prediction of the facial appearance following orthognathic surgery. This method shows how inaccuracies in the modelling and uncertainties in executing surgical planning influence the soft tissue prediction and it provides a range of predictions including a minimum and maximum, which may be helpful for patients in understanding the impact of surgery on the face.

In silico identification of novel kinase inhibitors targeting wild-type and T315I mutant ABL1 from FDA-approved drugs.

PubMed

Xu, Huai-long; Wang, Zi-jie; Liang, Xiao-meng; Li, Xin; Shi, Zheng; Zhou, Nan; Bao, Jin-ku

2014-06-01

The constitutively active fusion protein BCR-ABL1 is the major cause of chronic myeloid leukemia (CML), and selective inhibition of ABL1 is a promising approach for the treatment of CML. Reported drugs worked well in clinical practice, such as imatinib, dasatinib, nilotinib and bosutinib. However, resistance arises due to ABL1 mutation in patients, especially the T315I gate-keeper mutation. Thus, wide spectrum drugs targeting ABL1 are urgently needed. In order to screen potential drugs targeting wild-type ABL1 and T315I mutant ABL1, 1408 FDA approved small molecule drugs were subjected to molecular docking. With subsequent molecular dynamic (MD) simulation and MM/GBSA binding free energy calculation and energy decomposition, we identified chlorhexidine and sorafenib as potential "new use" drugs targeting wild-type ABL1, while nicergoline and plerixafor targeted T315I ABL1. Meanwhile, we also found that residues located in the ATP-binding site and A-loop motif played key roles in drug discovery towards ABL1. These findings may not only serve as a paradigm for the repositioning of existing approved drugs, but also instill new vitality to ABL1-targeted anti-CML therapeutics.

Repositioning of drugs using open-access data portal DTome: A test case with probenecid (Review).

PubMed

Ahmed, Mohammad U; Bennett, Dylan J; Hsieh, Tze-Chen; Doonan, Barbara B; Ahmed, Saba; Wu, Joseph M

2016-01-01

The one gene-one enzyme hypothesis, first introduced by Beadle and Tatum in the 1940s and based on their genetic analysis and observation of phenotype changes in Neurospora crassa challenged by various experimental conditions, has witnessed significant advances in recent decades. Much of our understanding of the association between genes and their phenotype expression has benefited from the completion of the human genome project, and has shown continual transformation guided by the effort directed at the annotation and characterization of human genes. Similarly, the idea of one drug‑one primary disease indication that traditionally has been the benchmark for the labeling and usage of drugs has also undergone evident progressive refinements; in recent years the science and practice of pharmaceutical development has notable success in the strategy of drug repurposing. Drug repurposing is an innovative approach where, instead of de novo synthesis and discovery of new drugs with novel indications, drug candidates with the desired usage are identified by a process of re‑profiling using an open‑source database or knowledge of known or failed drugs already in existence. In the present study, the repurposing drug strategy employing open‑access data portal drug‑target interactome (DTome) is applied to the uncovering of new clinical usage for probenecid.

Use of modified lip repositioning technique associated with esthetic crown lengthening for treatment of excessive gingival display: A case report of multiple etiologies

PubMed Central

Mantovani, Matheus Bortoluzzi; Souza, Eduardo Clemente; Marson, Fabiano Carlos; Corrêa, Giovani Oliveira; Progiante, Patrícia Saram; Silva, Cléverson Oliveira

2016-01-01

Excessive gingival display during smile can result in compromised esthetics. This study aims to report a case of excessive gingival display with multiple etiologies treated by means of modified lip repositioning technique associated with esthetic crown lengthening. A 23-year-old female patient, with 5-mm gingival display during smile caused by altered passive eruption and hypermobility of the upper lip, underwent the modified lip repositioning technique associated with gingivectomy followed by flap elevation and ostectomy/osteoplasty. Seven months after the second procedure, the patient had her esthetic complaint solved appearing stable in the observation period. The modified lip repositioning technique is an effective procedure employed to reduce gingival display and when associated with esthetic clinical crown lengthening, can appropriately treat cases of gummy smile. PMID:27041845

A cost-effectiveness analysis of two different repositioning strategies for the prevention of pressure ulcers.

PubMed

Marsden, Grace; Jones, Katie; Neilson, Julie; Avital, Liz; Collier, Mark; Stansby, Gerard

2015-12-01

To assess the cost effectiveness of two repositioning strategies and inform the 2014 National Institute for Health and Care Excellence clinical guideline recommendations on pressure ulcer prevention. Pressure ulcers are distressing events, caused when skin and underlying tissues are placed under pressure sufficient to impair blood supply. They can have a substantial impact on quality of life and have significant resource implications. Repositioning is a key prevention strategy, but can be resource intensive, leading to variation in practice. This economic analysis was conducted to identify the most cost-effective repositioning strategy for the prevention of pressure ulcers. The economic analysis took the form of a cost-utility model. The clinical inputs to the model were taken from a systematic review of clinical data. The population in the model was older people in a nursing home. The economic model was developed with members of the guideline development group and included costs borne by the UK National Health Service. Outcomes were expressed as costs and quality adjusted life years. Despite being marginally more clinically effective, alternating 2 and 4 hourly repositioning is not a cost-effective use of UK National Health Service resources (compared with 4 hourly repositioning) for this high risk group of patients at a cost-effectiveness threshold of £20,000 per quality adjusted life years. These results were used to inform the clinical guideline recommendations for those who are at high risk of developing pressure ulcers. © 2015 John Wiley & Sons Ltd.

Head repositioning accuracy in patients with neck pain and asymptomatic subjects: concurrent validity, influence of motion speed, motion direction and target distance.

PubMed

Dugailly, Pierre-Michel; De Santis, Roberta; Tits, Mathieu; Sobczak, Stéphane; Vigne, Anna; Feipel, Véronique

2015-12-01

Cervicocephalic kinesthetic deficiencies have been demonstrated in patients with chronic neck pain (NP). On the other hand, authors emphasized the use of different motion speeds for assessing functional impairment of the cervical spine. The objectives of this study were (1) to investigate the head repositioning accuracy in NP patients and control subjects and (2) to assess the influence of target distance, motion speed, motion direction and pain. Seventy-one subjects (36 healthy subjects and 35 NP patients; age 30-55 years) performed the head repositioning test (HRT) at two different speeds for horizontal and vertical movements and at two different distances. For each condition, six consecutive trials were sampled. The study showed the validity and reproducibility of the HRT, confirming a dysfunctional threshold of 4.5°. Normative values of head repositioning error up to 3.6° and 7.1° were identified for healthy and NP subjects, respectively. A distance of 180 cm from the target and a natural motion speed increased HRT accuracy. Repositioning after extension movement showed a significantly larger error in both groups. Intensity, duration of pain as well as pain level did not significantly alter head repositioning error. The assessment of proprioceptive performance in healthy and NP subjects allowed the validation of the HRT. The HRT is a simple, not expensive and fast test, easily implementable in daily practice to assess and monitor treatment and evolution of proprioceptive cervical deficits.

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

PubMed Central

Peng, Liang; Wu, Chun-Hua; Cao, Hong; Zhong, John F.; Hoffman, Jill; Huang, Sheng-He

2015-01-01

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer’s disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways. PMID:25993608

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli-Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses.

PubMed

Yu, Jing-Yi; Zhang, Bao; Peng, Liang; Wu, Chun-Hua; Cao, Hong; Zhong, John F; Hoffman, Jill; Huang, Sheng-He

2015-01-01

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer's disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.

Exploring the associations between drug side-effects and therapeutic indications.

PubMed

Wang, Fei; Zhang, Ping; Cao, Nan; Hu, Jianying; Sorrentino, Robert

2014-10-01

Drug therapeutic indications and side-effects are both measurable patient phenotype changes in response to the treatment. Inferring potential drug therapeutic indications and identifying clinically interesting drug side-effects are both important and challenging tasks. Previous studies have utilized either chemical structures or protein targets to predict indications and side-effects. In this study, we compared drug therapeutic indication prediction using various information including chemical structures, protein targets and side-effects. We also compared drug side-effect prediction with various information sources including chemical structures, protein targets and therapeutic indication. Prediction performance based on 10-fold cross-validation demonstrates that drug side-effects and therapeutic indications are the most predictive information source for each other. In addition, we extracted 6706 statistically significant indication-side-effect associations from all known drug-disease and drug-side-effect relationships. We further developed a novel user interface that allows the user to interactively explore these associations in the form of a dynamic bipartitie graph. Many relationship pairs provide explicit repositioning hypotheses (e.g., drugs causing postural hypotension are potential candidates for hypertension) and clear adverse-reaction watch lists (e.g., drugs for heart failure possibly cause impotence). All data sets and highly correlated disease-side-effect relationships are available at http://astro.temple.edu/∼tua87106/druganalysis.html. Copyright © 2014 Elsevier Inc. All rights reserved.

Novel ultrasound method to reposition kidney stones

PubMed Central

Shah, Anup; Owen, Neil R.; Lu, Wei; Cunitz, Bryan W.; Kaczkowski, Peter J.; Harper, Jonathan D.; Bailey, Michael R.; Crum, Lawrence A.

2011-01-01

The success of surgical management of lower pole stones is principally dependent on stone fragmentation and residual stone clearance. Choice of surgical method depends on stone size, yet all methods are subject to post-surgical complications resulting from residual stone fragments. Here we present a novel method and device to reposition kidney stones using ultrasound radiation force delivered by focused ultrasound and guided by ultrasound imaging. The device couples a commercial imaging array with a focused annular array transducer. Feasibility of repositioning stones was investigated by implanting artificial and human stones into a kidney-mimicking phantom that simulated a lower pole and collecting system. During experiment, stones were located by ultrasound imaging and repositioned by delivering short bursts of focused ultrasound. Stone motion was concurrently monitored by fluoroscopy, ultrasound imaging, and video photography, from which displacement and velocity were estimated. Stones were seen to move immediately after delivering focused ultrasound and successfully repositioned from the lower pole to the collecting system. Estimated velocities were on the order of 1 cm/s. This in vitro study demonstrates a promising modality to facilitate spontaneous clearance of kidney stones and increased clearance of residual stone fragments after surgical management. PMID:20967437

Ultrasonic propulsion of kidney stones.

PubMed

May, Philip C; Bailey, Michael R; Harper, Jonathan D

2016-05-01

Ultrasonic propulsion is a novel technique that uses short bursts of focused ultrasonic pulses to reposition stones transcutaneously within the renal collecting system and ureter. The purpose of this review is to discuss the initial testing of effectiveness and safety, directions for refinement of technique and technology, and opinions on clinical application. Preclinical studies with a range of probes, interfaces, and outputs have demonstrated feasibility and consistent safety of ultrasonic propulsion with room for increased outputs and refinement toward specific applications. Ultrasonic propulsion was used painlessly and without adverse events to reposition stones in 14 of 15 human study participants without restrictions on patient size, stone size, or stone location. The initial feasibility study showed applicability in a range of clinically relevant situations, including facilitating passage of residual fragments following ureteroscopy or shock wave lithotripsy, moving a large stone at the ureteropelvic junction with relief of pain, and differentiating large stones from a collection of small fragments. Ultrasonic propulsion shows promise as an office-based system for transcutaneously repositioning kidney stones. Potential applications include facilitating expulsion of residual fragments following ureteroscopy or shock wave lithotripsy, repositioning stones prior to treatment, and repositioning obstructing ureteropelvic junction stones into the kidney to alleviate acute renal colic.

Ultrasonic propulsion of kidney stones

PubMed Central

May, Philip C.; Bailey, Michael R.; Harper, Jonathan D.

2016-01-01

Purpose of review Ultrasonic propulsion is a novel technique that uses short bursts of focused ultrasonic pulses to reposition stones transcutaneously within the renal collecting system and ureter. The purpose of this review is to discuss the initial testing of effectiveness and safety, directions for refinement of technique and technology, and opinions on clinical application. Recent findings Preclinical studies with a range of probes, interfaces, and outputs have demonstrated feasibility and consistent safety of ultrasonic propulsion with room for increased outputs and refinement toward specific applications. Ultrasonic propulsion was used painlessly and without adverse events to reposition stones in 14 of 15 human study participants without restrictions on patient size, stone size, or stone location. The initial feasibility study showed applicability in a range of clinically relevant situations, including facilitating passage of residual fragments following ureteroscopy or shock wave lithotripsy, moving a large stone at the UPJ with relief of pain, and differentiating large stones from a collection of small fragments. Summary Ultrasonic propulsion shows promise as an office-based system for transcutaneously repositioning kidney stones. Potential applications include facilitating expulsion of residual fragments following ureteroscopy or shock wave lithotripsy, repositioning stones prior to treatment, and repositioning obstructing UPJ stones into the kidney to alleviate acute renal colic. PMID:26845428

Efficacy of medical therapy in the prevention of residual dizziness after successful repositioning maneuvers for Benign Paroxysmal Positional Vertigo (BPPV).

PubMed

Acar, B; Karasen, R M; Buran, Y

2015-01-01

The aim of this study was to investigate the efficacy of trimetazidine, betahistine, and ginkgo biloba extract in the treatment of residual dizziness after successful repositioning maneuvers for benign paroxysmal positional vertigo. This was a randomized controlled clinical trial. Complete clinical data were analyzed from 100 patients (27 men and 73 women; mean age 52.16 ± 13.2 years, range 11-80 years) with BPPV who underwent succcessful repositioning maneuvers and then received betahistine, trimetazidine, gingko biloba extract, or no medication (n = 25 for each group) for 1 week. On days 1, 3, and 5 after the repositioning maneuver, scores obtained from the Dizziness Handicap Inventory (DHI) questionnaire were compared. There were no statistically significant differences in the premedication DHI scores of patients with residual dizziness among the four groups (p > 0.005). After 3 and 5 days of treatment, the mean DHI scores of the groups receiving medication did not differ significantly from the the mean DHI score of the control group (p > 0.005). Our study results suggest that betahistine, trimetazidine, and gingko biloba extract do not alleviate residual dizziness after successful repositioning maneuvers.

Nudging at the checkout counter - A longitudinal study of the effect of a food repositioning nudge on healthy food choice.

PubMed

Van Gestel, L C; Kroese, F M; De Ridder, D T D

2018-06-01

Objective The current study is a longitudinal conceptual replication and aimed to investigate the effect of a food repositioning nudge on healthy food choice in a kiosk. Design During eight weeks, sales data were collected. The former four weeks formed the baseline phase and the latter four weeks formed the nudge phase where healthy food products were repositioned at the checkout counter display, while unhealthy alternatives remained available elsewhere in the store. Main Outcome Measures The main variable of interest was the proportion of healthy food products (selected to be repositioned) sold per day. Also exit interviews were administered to gather individual level data about purchases, and awareness and opinions of the nudge. Results Results showed that the proportion of selected healthy food products in total food sales was higher in all four nudge weeks than in all four baseline weeks. Individual level data showed that more customers had bought a selected healthy food product in the nudge phase and that customers generally approved of the nudge. Conclusion The current study strengthened the empirical evidence base of repositioning healthy food products as an effective and well-accepted nudge.

oVEMP as an objective indicator of successful repositioning maneuver.

PubMed

Asal, Samir; Sobhy, Osama; Balbaa, Amany

Benign paroxysmal positioning vertigo (BPPV) is the most common peripheral vestibular disorder. Canalolithiasis in the posterior semi-circular canal is the most common underlying pathology that can be treated effectively by repositioning maneuvers. Our hypothesis suggested that successful maneuvers can lead to repositioning of dislodged otoconia to the utricle. Air conducted oVEMP, which is thought to originate from the contra-lateral utricular organ was measured in twenty patients with unilateral BPPV and we compared n1-p1 peak to peak amplitude of the affected ears in 3 separate intervals: on pre-treatment when typical nystagmus was confirmed, immediately after, and 1 week after repositioning maneuvers to assess change, if any, in amplitude. This study showed significant increase of oVEMP amplitude in the affected ears after successful repositioning maneuver that was more significant after 1 week. oVEMP can be used as a reliable objective test for ensuring a successful maneuver rather than subjective dependence on the patient's symptoms, which may be misleading due to a remission. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

Orthognathic positioning system: intraoperative system to transfer virtual surgical plan to operating field during orthognathic surgery.

PubMed

Polley, John W; Figueroa, Alvaro A

2013-05-01

To introduce the concept and use of an occlusal-based "orthognathic positioning system" (OPS) to be used during orthognathic surgery. The OPS consists of intraoperative occlusal-based devices that transfer virtual surgical planning to the operating field for repositioning of the osteotomized dentoskeletal segments. The system uses detachable guides connected to an occlusal splint. An initial drilling guide is used to establish stable references or landmarks. These are drilled on the bone that will not be repositioned adjacent to the osteotomy line. After mobilization of the skeletal segment, a final positioning guide, referenced to the drilled landmarks, is used to transfer the skeletal segment according to the virtual surgical planning. The OPS is digitally designed using 3-dimensional computer-aided design/computer-aided manufacturing technology and manufactured with stereolithographic techniques. Virtual surgical planning has improved the preoperative assessment and, in conjunction with the OPS, the execution of orthognathic surgery. The OPS has the possibility to eliminate the inaccuracies commonly associated with traditional orthognathic surgery planning and to simplify the execution by eliminating surgical steps such as intraoperative measuring, determining the condylar position, the use of bulky intermediate splints, and the use of intermaxillary wire fixation. The OPS attempts precise translation of the virtual plan to the operating field, bridging the gap between virtual and actual surgery. Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Nonpharmacologic Interventions to Prevent Pressure Ulcers in Older Patients: An Overview of Systematic Reviews (The Software ENgine for the Assessment and optimization of drug and non-drug Therapy in Older peRsons [SENATOR] Definition of Optimal Evidence-Based Non-drug Therapies in Older People [ONTOP] Series).

PubMed

Lozano-Montoya, Isabel; Vélez-Díaz-Pallarés, Manuel; Abraha, Iosief; Cherubini, Antonio; Soiza, Roy L; O'Mahony, Denis; Montero-Errasquín, Beatriz; Correa-Pérez, Andrea; Cruz-Jentoft, Alfonso J

2016-04-01

Pressure ulcers (PUs) are frequent in older patients, and the healing process is usually challenging, therefore, prevention should be the first strategic line in PU management. Nonpharmacologic interventions may play a role in the prevention of PUs in older people, but most systematic reviews (SRs) have not addressed this specific population using convincing outcome measures. To summarize and critically appraise the evidence from SRs of the primary studies on nonpharmacologic interventions to prevent PUs in older patients. SR and meta-analysis of comparative studies. PubMed, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL (from inception to October 2013) were searched. A new search for updates in the Cochrane Database was launched in July 2014. SRs that included at least 1 comparative study evaluating any nonpharmacologic intervention to prevent PUs in older patients, in any healthcare setting, were selected. Any primary study with experimental design was then identified and included. From each primary study, quality assessment was undertaken as specified by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. Interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis, using the incidence of new pressure ulcers as the main outcome measure. One hundred ten SRs with 65 primary studies satisfied the inclusion criteria. The most frequent interventions explored in these trials were support surfaces (41 studies), repositioning (8), and nutrition interventions (5). High quality of evidence was not found for any intervention, mainly because of a high risk of bias and imprecision. There is moderate quality evidence to support the use of alternating pressure support mattresses over usual hospital mattresses in medical and surgical inpatients, low quality evidence to support constant low pressure devices and Australian medical sheepskin over usual mattresses, and very low quality evidence to support nutrition interventions in hospital settings. No recommendations on hydration, repositioning, standardized risk assessment, or multicomponent interventions can be done. In older patients at high risk to suffer PUs, high-technology and low- technology support surfaces can significantly reduce the incidence of PUs. Nutrition intervention may also have a role in preventing PUs in hospital settings. More evidence is needed to support other recommendations, which is specially lacking for repositioning. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Effect of body repositioning after venous air embolism. An echocardiographic study

NASA Technical Reports Server (NTRS)

Geissler, H. J.; Allen, S. J.; Mehlhorn, U.; Davis, K. L.; Morris, W. P.; Butler, B. D.

1997-01-01

BACKGROUND: Current therapy for massive venous air embolism (VAE) may include the use of the left lateral recumbent (LLR) position, although its effectiveness has been questioned. This study used transesophageal echocardiography to evaluate the effect of body repositioning on intracardiac air and acute cardiac dimension changes. METHODS: Eighteen anesthetized dogs in the supine position received a venous air injection of 2.5 ml/kg at a rate of 5 ml/ s. After 1 min the dogs were repositioned into either the LLR, LLR 10 degrees head down (LLR-10 degrees), right lateral recumbence, or remained in the supine position. RESULTS: Repositioning after VAE resulted in relocation of intracardiac air to nondependent areas of the right heart. Peak right ventricular (RV) diameter increase and mean arterial pressure decrease were greater in the repositioned animals compared with those in the supine position (P < 0.05). Right ventricular diameter and mean arterial pressure showed an inverse correlation (r = 0.81). Peak left atrial diameter decrease was greater in the LLR and LLR-10 degrees positions compared with the supine position (P < 0.05). Repositioning did not influence peak pulmonary artery pressure increase, and no correlation was found between RV diameter and pulmonary artery pressure. All animals showed electrocardiogram and echocardiographic changes reconcilable with myocardial ischemia. CONCLUSIONS: In dogs, body repositioning after VAE provided no benefit in hemodynamic performance or cardiac dimension changes, although relocation of intracardiac air was demonstrated. Right ventricular air did not appear to result in significant RV outflow obstruction, as pulmonary artery pressure increased uniformly in all groups and was not influenced by the relocation of intracardiac air. The combination of increased RV afterload and arterial hypotension, possibly with subsequent RV ischemia rather than RV outflow obstruction by an airlock appeared to be the primary mechanism for cardiac dysfunction after VAE.

Turning for Ulcer Reduction (TURN) Study: An Economic Analysis.

PubMed

Paulden, Mike; Bergstrom, Nancy; Horn, Susan D; Rapp, Mary; Stern, Anita; Barrett, Ryan; Watkiss, Michael; Krahn, Murray

2014-01-01

The Turning for Ulcer Reduction (TURN) study was a multisite, randomized controlled trial that aimed to determine the optimal frequency of turning nursing facility residents with mobility limitations who are at moderate and high risk for pressure ulcer (PrU) development. Here we present data from the economic analysis. This economic analysis aims to estimate the economic consequences for Ontario of switching from a repositioning schedule of 2-hour intervals to a schedule of 3-hour or 4-hour intervals. Costs considered in the analysis included those associated with nursing staff time spent repositioning residents and with incontinent care supplies, which included briefs, barrier cream, and washcloths. The total economic benefit of switching to 3-hour or 4-hour repositioning is estimated to be $11.05 or $16.74 per day, respectively, for every resident at moderate or high risk of developing PrUs. For a typical facility with 123 residents, 41 (33%) of whom are at moderate or high risk of developing PrUs, the total economic benefit is estimated to be $453 daily for 3-hour or $686 daily for 4-hour repositioning. For Ontario as a whole, assuming that there are 77,933 residents at 634 LTC facilities, 25,927 (33%) of whom are at moderate or high risk of developing PrUs, the total economic benefits of switching to 3-hour or 4-hour repositioning are estimated to be $286,420 or $433,913 daily, respectively, equivalent to $104.5 million or $158.4 million per year. We did not consider the savings the Ontario Ministry of Health and Long-Term Care might incur should less frequent repositioning reduce the incidence of work-related injury among nursing staff, so our findings are potentially conservative. A switch to 3-hour or 4-hour repositioning appears likely to yield substantial economic benefits to Ontario without placing residents at greater risk of developing PrUs.

Turning for Ulcer Reduction (TURN) Study: An Economic Analysis

PubMed Central

Paulden, Mike; Bergstrom, Nancy; Horn, Susan D.; Rapp, Mary; Stern, Anita; Barrett, Ryan; Watkiss, Michael; Krahn, Murray

2014-01-01

Background The Turning for Ulcer Reduction (TURN) study was a multisite, randomized controlled trial that aimed to determine the optimal frequency of turning nursing facility residents with mobility limitations who are at moderate and high risk for pressure ulcer (PrU) development. Here we present data from the economic analysis. Objectives This economic analysis aims to estimate the economic consequences for Ontario of switching from a repositioning schedule of 2-hour intervals to a schedule of 3-hour or 4-hour intervals. Data Sources Costs considered in the analysis included those associated with nursing staff time spent repositioning residents and with incontinent care supplies, which included briefs, barrier cream, and washcloths. Results The total economic benefit of switching to 3-hour or 4-hour repositioning is estimated to be $11.05 or $16.74 per day, respectively, for every resident at moderate or high risk of developing PrUs. For a typical facility with 123 residents, 41 (33%) of whom are at moderate or high risk of developing PrUs, the total economic benefit is estimated to be $453 daily for 3-hour or $686 daily for 4-hour repositioning. For Ontario as a whole, assuming that there are 77,933 residents at 634 LTC facilities, 25,927 (33%) of whom are at moderate or high risk of developing PrUs, the total economic benefits of switching to 3-hour or 4-hour repositioning are estimated to be $286,420 or $433,913 daily, respectively, equivalent to $104.5 million or $158.4 million per year. Limitations We did not consider the savings the Ontario Ministry of Health and Long-Term Care might incur should less frequent repositioning reduce the incidence of work-related injury among nursing staff, so our findings are potentially conservative. Conclusions A switch to 3-hour or 4-hour repositioning appears likely to yield substantial economic benefits to Ontario without placing residents at greater risk of developing PrUs. PMID:26330894

Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis.

PubMed

Liu, Lei; Tsompana, Maria; Wang, Yong; Wu, Dingfeng; Zhu, Lixin; Zhu, Ruixin

2016-09-26

Drug discovery and development is a costly and time-consuming process with a high risk for failure resulting primarily from a drug's associated clinical safety and efficacy potential. Identifying and eliminating inapt candidate drugs as early as possible is an effective way for reducing unnecessary costs, but limited analytical tools are currently available for this purpose. Recent growth in the area of toxicogenomics and pharmacogenomics has provided with a vast amount of drug expression microarray data. Web servers such as CMap and LTMap have used this information to evaluate drug toxicity and mechanisms of action independently; however, their wider applicability has been limited by the lack of a combinatorial drug-safety type of analysis. Using available genome-wide drug transcriptional expression profiles, we developed the first web server for combinatorial evaluation of toxicity and efficacy of candidate drugs named "Connection Map for Compounds" (CMC). Using CMC, researchers can initially compare their query drug gene signatures with prebuilt gene profiles generated from two large-scale toxicogenomics databases, and subsequently perform a drug efficacy analysis for identification of known mechanisms of drug action or generation of new predictions. CMC provides a novel approach for drug repositioning and early evaluation in drug discovery with its unique combination of toxicity and efficacy analyses, expansibility of data and algorithms, and customization of reference gene profiles. CMC can be freely accessed at http://cadd.tongji.edu.cn/webserver/CMCbp.jsp .

A new head holder for reducing axial movement and repositioning errors during physiological CT imaging.

PubMed

Shrawder, S; Lapin, G D; Allen, C V; Vick, N A; Groothuis, D R

1994-01-01

We designed a new head holder for immobilization and repositioning in dynamic CT studies of the brain. A customized thermoplastic face mask and foam head rest were made to restrict movement of the head in all directions, but particularly out of the axial plane (z-movement). This design provided a rigid, detailed mold of the face and back of the head that minimized motion during lengthy CT studies and enabled accurate repositioning of the head for follow-up studies. Markers applied directly to the skin were used to quantify z-movement. When tested on 12 subjects, immobilization was limited to < 2.0 mm under worst-case conditions when the subject was asked to attempt forced movements. Repositioning was accurate to < 1.5 mm when the subject was removed from the head holder and then placed back into it.

Effects of nucleosome stability on remodeler-catalyzed repositioning

NASA Astrophysics Data System (ADS)

Morgan, Aaron M.; LeGresley, Sarah E.; Briggs, Koan; Al-Ani, Gada; Fischer, Christopher J.

2018-03-01

Chromatin remodelers are molecular motors that play essential roles in the regulation of nucleosome positioning and chromatin accessibility. These machines couple the energy obtained from the binding and hydrolysis of ATP to the mechanical work of manipulating chromatin structure through processes that are not completely understood. Here we present a quantitative analysis of nucleosome repositioning by the imitation switch (ISWI) chromatin remodeler and demonstrate that nucleosome stability significantly impacts the observed activity. We show how DNA damage induced changes in the affinity of DNA wrapping within the nucleosome can affect ISWI repositioning activity and demonstrate how assay-dependent limitations can bias studies of nucleosome repositioning. Together, these results also suggest that some of the diversity seen in chromatin remodeler activity can be attributed to the variations in the thermodynamics of interactions between the remodeler, the histones, and the DNA, rather than reflect inherent properties of the remodeler itself.

Using Composite Resin Inclined Plane for the Repositioning of a Laterally Luxated Primary Incisor: A Case Report

PubMed Central

Arikan, Volkan; Sari, Saziye

2011-01-01

This case report describes the repositioning of a laterally luxated primary central incisor with occlusal interference, using a composite inclined plane. The patient was a 4-year-old girl who applied to our clinic three days after the injury. Because of the time delay between injury and presentation, it was not possible to reposition the tooth with pressure. Following a root-canal treatment, an inclined plane was prepared on the lower primary incisors, using composite resin. The tooth was repositioned in two weeks, and the inclined plane was then removed. After 1 year of follow-up, the treatment was found to be successful, both clinically and radiographically. The use of a composite inclined plane, accompanied by careful follow-up, is an effective alternative to extraction for laterally luxated primary incisors with occlusal interference. PMID:21228962

Repurposing anticancer drugs for targeting necroptosis.

PubMed

Fulda, Simone

2018-04-25

Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases. Thus, targeted interference with necroptosis signaling may offer new opportunities for the treatment of human diseases. Besides structure-based drug design, in recent years drug repositioning has emerged as a promising alternative to develop drug-like compounds. There is accumulating evidence showing that multi-targeting kinase inhibitors, for example Dabrafenib, Vemurafenib, Sorafenib, Pazopanib and Ponatinib, used for the treatment of cancer also display anti-necroptotic activity. This review summarizes recent evidence indicating that some anticancer kinase inhibitors also negatively affect necroptosis signaling. This implies that some cancer therapeutics may be repurposed for other pathologies, e.g. ischemic or inflammatory diseases.

CancerHSP: anticancer herbs database of systems pharmacology

NASA Astrophysics Data System (ADS)

Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

2015-06-01

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

‘I’m still a hustler’: entrepreneurial responses to precarity by participants in phase I clinical trials

PubMed Central

Monahan, Torin; Fisher, Jill A.

2016-01-01

This paper questions the implications of entrepreneurial responses to conditions of employment precarity by ‘healthy volunteers’ in phase I clinical trials in the United States. Such individuals are typically serial participants who often identify as professional volunteers and seek out drug studies as their primary source of income. Drawing on extensive qualitative research, this paper illustrates how healthy volunteers selectively import the identity of ‘hustler’ from the street environment and reposition it as connoting a set of valuable creative skills that give them a competitive edge over other participants. An entrepreneurial ethos allows them to view personal sacrifice and exposure to potentially dangerous drugs as smart investments leading to financially stable futures. These discursive moves normalize extractive, and at times dehumanizing, labour relations that offload expenses and risks to workers. PMID:27524854

'I'm still a hustler': entrepreneurial responses to precarity by participants in phase I clinical trials.

PubMed

Monahan, Torin; Fisher, Jill A

This paper questions the implications of entrepreneurial responses to conditions of employment precarity by 'healthy volunteers' in phase I clinical trials in the United States. Such individuals are typically serial participants who often identify as professional volunteers and seek out drug studies as their primary source of income. Drawing on extensive qualitative research, this paper illustrates how healthy volunteers selectively import the identity of 'hustler' from the street environment and reposition it as connoting a set of valuable creative skills that give them a competitive edge over other participants. An entrepreneurial ethos allows them to view personal sacrifice and exposure to potentially dangerous drugs as smart investments leading to financially stable futures. These discursive moves normalize extractive, and at times dehumanizing, labour relations that offload expenses and risks to workers.

Minimal Invasive Left Ventricular Lead Repositioning is Safe and Effective in Distal Left Ventricular Lead Positions.

PubMed

Osztheimer, István; Szilágyi, Szabolcs; Pongor, Zsuzsanna; Zima, Endre; Molnár, Levente; Tahin, Tamás; Merkely, Béla; Gellér, László

2017-05-01

Treatment of left ventricular electrode dislocation and phrenic nerve stimulation remains an issue in the era of new electrode designs. Safety and efficacy of minimal invasive lead repositioning and pocket opening reposition procedures were evaluated between December 2005 and December 2012 at our center. Minimal invasive method was developed and widely utilized at our center to treat phrenic nerve stimulation. The distally positioned left ventricular lead is looped around by a deflectable catheter in the right atrium introduced from the femoral vein access and then pulled back. Coronary stent implantation was used afterwards for lead stabilization in some patients. 42 minimal invasive and 48 electrode repositions with pacemaker pocket opening were performed at 77 patients for left ventricular lead problems. Minimal invasive reposition could be carried out successfully in 69% of (29 patients) cases. Note that in 14.3% of the cases (six patients) minimal invasive procedures were acutely unsuccessful and crossover was necessary. In 16.6% of the cases (seven patients) lead issues were noted later during follow-up. Opening of the pocket could be carried out successfully in 81.2% (39 patients) and was unsuccessful acutely in 6.25% (three patients). Repeated dislocation was noticed, 12.5%, in this group (six patients). Complication during minimal invasive procedures was electrode injury in one case. Pocket openings were associated with several complications: atrial fibrillation, pericardial effusion, fever, hematoma, and right ventricular electrode dislodgement. Minimal invasive procedure-as the first line approach-is safe and feasible for left ventricular electrode repositioning in selected cases. © 2017 Wiley Periodicals, Inc.

The physiological response of soft tissue to periodic repositioning as a strategy for pressure ulcer prevention.

PubMed

Woodhouse, Marjolein; Worsley, Peter R; Voegeli, David; Schoonhoven, Lisette; Bader, Dan L

2015-02-01

Individuals who have reduced mobility are at risk of developing pressure ulcers if they are subjected to sustained static postures. To reduce this risk, clinical guidelines advocate healthcare professionals reposition patients regularly. Automated tilting mechanisms have recently been introduced to provide periodic repositioning. This study compared the performance of such a prototype mattress to conventional manual repositioning. Ten healthy participants (7 male and 3 female, aged 23-66 years) were recruited to compare the effects of an automated tilting mattress to standard manual repositioning, using the 30° tilt. Measures during the tilting protocols (supine, right and left tilt) included comfort and safety scores, interface pressures, inclinometer angles and transcutaneous gas tensions (sacrum and shoulder). Data from these outcomes were compared between each protocol. Results indicated no significant differences for either interface pressures or transcutaneous gas responses between the two protocols (P>0.05 in both cases). Indeed a small proportion of participants (~30%) exhibited changes in transcutaneous oxygen and carbon dioxide values in the shoulder during a right tilt for both protocols. The tilt angles at the sternum and the pelvis were significantly less in the automated tilt compared to the manual tilt (mean difference=9.4-11.5°, P<0.001). Participants reported similar comfort scores for both protocols, although perceived safety was reduced on the prototype mattress. Although further studies are required to assess its performance in maintaining tissue viability, an automated tilting mattress offers the ability to periodically reposition vulnerable individuals, with potential economic savings to health services. Copyright © 2014 Elsevier Ltd. All rights reserved.

Auditory Proprioceptive Integration: Effects of Real-Time Kinematic Auditory Feedback on Knee Proprioception

PubMed Central

Ghai, Shashank; Schmitz, Gerd; Hwang, Tong-Hun; Effenberg, Alfred O.

2018-01-01

The purpose of the study was to assess the influence of real-time auditory feedback on knee proprioception. Thirty healthy participants were randomly allocated to control (n = 15), and experimental group I (15). The participants performed an active knee-repositioning task using their dominant leg, with/without additional real-time auditory feedback where the frequency was mapped in a convergent manner to two different target angles (40 and 75°). Statistical analysis revealed significant enhancement in knee re-positioning accuracy for the constant and absolute error with real-time auditory feedback, within and across the groups. Besides this convergent condition, we established a second divergent condition. Here, a step-wise transposition of frequency was performed to explore whether a systematic tuning between auditory-proprioceptive repositioning exists. No significant effects were identified in this divergent auditory feedback condition. An additional experimental group II (n = 20) was further included. Here, we investigated the influence of a larger magnitude and directional change of step-wise transposition of the frequency. In a first step, results confirm the findings of experiment I. Moreover, significant effects on knee auditory-proprioception repositioning were evident when divergent auditory feedback was applied. During the step-wise transposition participants showed systematic modulation of knee movements in the opposite direction of transposition. We confirm that knee re-positioning accuracy can be enhanced with concurrent application of real-time auditory feedback and that knee re-positioning can modulated in a goal-directed manner with step-wise transposition of frequency. Clinical implications are discussed with respect to joint position sense in rehabilitation settings. PMID:29568259

Uneven drive rates of the scanning telescope: Apollo 16 mission

NASA Technical Reports Server (NTRS)

1972-01-01

An investigation was made into the cause or causes of uneven drive rates during operation of the Apollo 16 scanning telescope. It was suggested that such erratic behavior was caused by either changes in the characteristics noise level of the optics counter on the panels or the repositioning process by the computer or zero optics mode. Test results show the anomaly was not caused by either of the above suggestions, instead they were caused by a broken socket spring in the telescope harness. New harnesses will be manufactured for future flights.

More-Realistic Digital Modeling of a Human Body

NASA Technical Reports Server (NTRS)

Rogge, Renee

2010-01-01

A MATLAB computer program has been written to enable improved (relative to an older program) modeling of a human body for purposes of designing space suits and other hardware with which an astronaut must interact. The older program implements a kinematic model based on traditional anthropometric measurements that do provide important volume and surface information. The present program generates a three-dimensional (3D) whole-body model from 3D body-scan data. The program utilizes thin-plate spline theory to reposition the model without need for additional scans.

Stereotactic radiotherapy for choroidal melanoma: analysis of eye movement during treatment

NASA Astrophysics Data System (ADS)

Souza, F. M. L.; Gonçalves, O. D.; Batista, D. V. S.; Cardoso, S. C.

2018-03-01

This study aims to analyse the eye’s movement during radiotherapy treatment for choroidal melanoma, as well as the methodology used in the repositioning of the patient between treatments sessions. For this purpose, the procedures used by the hospital staff were analysed on site and videos were recorded during the treatments. The methodology for the fixation of the eye is correct in its objective. However, the repositioning needs improvements in its reproducibility. It is recommended the study to fix the eye by the healthy eye and the feasibility study for the development of a software that assists in patient repositioning.

Reproducibility of patient positioning for fractionated extracranial stereotactic radiotherapy using a double-vacuum technique.

PubMed

Nevinny-Stickel, Meinhard; Sweeney, Reinhart A; Bale, Reto J; Posch, Andrea; Auberger, Thomas; Lukas, Peter

2004-02-01

Precise reproducible patient positioning is a prerequisite for conformal fractionated radiotherapy. A fixation system based on double-vacuum technology is presented which can be used for conventional as well as hypofractionated stereotactic extracranial radiotherapy. To form the actual vacuum mattress, the patient is pressed into the mattress with a vacuum foil which can also be used for daily repositioning and fixation. A stereotactic frame can be positioned over the region of interest on an indexed base plate. Repositioning accuracy was determined by comparing daily, pretreatment, orthogonal portal images to the respective digitally reconstructed radiographs (DRRs) in ten patients with abdominal and pelvic lesions receiving extracranial fractionated (stereotactic) radiotherapy. The three-dimensional (3-D) vectors and 95% confidence intervals (CI) were calculated from the respective deviations in the three axes. Time required for initial mold production and daily repositioning was also determined. The mean 3-D repositioning error (187 fractions) was 2.5 +/- 1.1 mm. The largest single deviation (10 mm) was observed in a patient treated in prone position. Mold production took an average of 15 min (10-30 min). Repositioning times are not necessarily longer than using no positioning aid at all. The presented fixation system allows reliable, flexible and efficient patient positioning for extracranial stereotactic radiotherapy.

Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity.

PubMed

Cowan, Noemi; Raimondo, Alessia; Keiser, Jennifer

2016-11-01

Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200-400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (>80 % drug effect at 50 μM). Ten of these drugs were also active on the adult worm stage (>80 % drug effect at 50 μM), of which six revealed IC 50 values between 1.8 and 5.0 μM. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0-24 % and worm expulsion rates of 0-7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered.

Drug Intervention Response Predictions with PARADIGM (DIRPP) identifies drug resistant cancer cell lines and pathway mechanisms of resistance.

PubMed

Brubaker, Douglas; Difeo, Analisa; Chen, Yanwen; Pearl, Taylor; Zhai, Kaide; Bebek, Gurkan; Chance, Mark; Barnholtz-Sloan, Jill

2014-01-01

The revolution in sequencing techniques in the past decade has provided an extensive picture of the molecular mechanisms behind complex diseases such as cancer. The Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Project (CGP) have provided an unprecedented opportunity to examine copy number, gene expression, and mutational information for over 1000 cell lines of multiple tumor types alongside IC50 values for over 150 different drugs and drug related compounds. We present a novel pipeline called DIRPP, Drug Intervention Response Predictions with PARADIGM7, which predicts a cell line's response to a drug intervention from molecular data. PARADIGM (Pathway Recognition Algorithm using Data Integration on Genomic Models) is a probabilistic graphical model used to infer patient specific genetic activity by integrating copy number and gene expression data into a factor graph model of a cellular network. We evaluated the performance of DIRPP on endometrial, ovarian, and breast cancer related cell lines from the CCLE and CGP for nine drugs. The pipeline is sensitive enough to predict the response of a cell line with accuracy and precision across datasets as high as 80 and 88% respectively. We then classify drugs by the specific pathway mechanisms governing drug response. This classification allows us to compare drugs by cellular response mechanisms rather than simply by their specific gene targets. This pipeline represents a novel approach for predicting clinical drug response and generating novel candidates for drug repurposing and repositioning.

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production

PubMed Central

Gillespie, Zoe E; MacKay, Kimberly; Sander, Michelle; Trost, Brett; Dawicki, Wojciech; Wickramarathna, Aruna; Gordon, John; Eramian, Mark; Kill, Ian R; Bridger, Joanna M; Kusalik, Anthony; Mitchell, Jennifer A; Eskiw, Christopher H

2015-01-01

Rapamycin is a well-known inhibitor of the Target of Rapamycin (TOR) signaling cascade; however, the impact of this drug on global genome function and organization in normal primary cells is poorly understood. To explore this impact, we treated primary human foreskin fibroblasts with rapamycin and observed a decrease in cell proliferation without causing cell death. Upon rapamycin treatment chromosomes 18 and 10 were repositioned to a location similar to that of fibroblasts induced into quiescence by serum reduction. Although similar changes in positioning occurred, comparative transcriptome analyses demonstrated significant divergence in gene expression patterns between rapamycin-treated and quiescence-induced fibroblasts. Rapamycin treatment induced the upregulation of cytokine genes, including those from the Interleukin (IL)-6 signaling network, such as IL-8 and the Leukemia Inhibitory Factor (LIF), while quiescent fibroblasts demonstrated up-regulation of genes involved in the complement and coagulation cascade. In addition, genes significantly up-regulated by rapamycin treatment demonstrated increased promoter occupancy of the transcription factor Signal Transducer and Activator of Transcription 5A/B (STAT5A/B). In summary, we demonstrated that the treatment of fibroblasts with rapamycin decreased proliferation, caused chromosome territory repositioning and induced STAT5A/B-mediated changes in gene expression enriched for cytokines. PMID:26652669

47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 4 2012-10-01 2012-10-01 false Deletion or repositioning of broadcast signals. 76.1601 Section 76.1601 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or...

47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 4 2013-10-01 2013-10-01 false Deletion or repositioning of broadcast signals. 76.1601 Section 76.1601 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or...

47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 4 2010-10-01 2010-10-01 false Deletion or repositioning of broadcast signals. 76.1601 Section 76.1601 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or...

47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 4 2011-10-01 2011-10-01 false Deletion or repositioning of broadcast signals. 76.1601 Section 76.1601 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or...

47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 4 2014-10-01 2014-10-01 false Deletion or repositioning of broadcast signals. 76.1601 Section 76.1601 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or...

Evidence of Impaired Proprioception in Chronic, Idiopathic Neck Pain: Systematic Review and Meta-Analysis

PubMed Central

Leake, Hayley B.; Chalmers, K. Jane; Moseley, G. Lorimer

2016-01-01

Background Despite common use of proprioceptive retraining interventions in people with chronic, idiopathic neck pain, evidence that proprioceptive dysfunction exists in this population is lacking. Determining whether proprioceptive dysfunction exists in people with chronic neck pain has clear implications for treatment prescription. Purpose The aim of this study was to synthesize and critically appraise all evidence evaluating proprioceptive dysfunction in people with chronic, idiopathic neck pain by completing a systematic review and meta-analysis. Data Sources MEDLINE, CINAHL, PubMed, Allied and Complementary Medicine, EMBASE, Academic Search Premier, Scopus, Physiotherapy Evidence Database (PEDro), and Cochrane Collaboration databases were searched. Study Selection All published studies that compared neck proprioception (joint position sense) between a chronic, idiopathic neck pain sample and asymptomatic controls were included. Data Extraction Two independent reviewers extracted relevant population and proprioception data and assessed methodological quality using a modified Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Data Synthesis Thirteen studies were included in the present review. Meta-analysis on 10 studies demonstrated that people with chronic neck pain perform significantly worse on head-to-neutral repositioning tests, with a moderate standardized mean difference of 0.44 (95% confidence interval=0.25, 0.63). Two studies evaluated head repositioning using trunk movement (no active head movement thus hypothesized to remove vestibular input) and showed conflicting results. Three studies evaluated complex or postural repositioning tests; postural repositioning was no different between groups, and complex movement tests were impaired only in participants with chronic neck pain if error was continuously evaluated throughout the movement. Limitations A paucity of studies evaluating complex or postural repositioning tests does not permit any solid conclusions about them. Conclusions People with chronic, idiopathic neck pain are worse than asymptomatic controls at head-to-neutral repositioning tests. PMID:26472296

Content and Face Validation of a Curriculum for Ultrasonic Propulsion of Calculi in a Human Renal Model

PubMed Central

Dunmire, Barbrina; Cunitz, Bryan W.; He, Xuemei; Sorensen, Mathew D.; Harper, Jonathan D.; Bailey, Michael R.; Lendvay, Thomas S.

2014-01-01

Abstract Purpose: Ultrasonic propulsion to reposition urinary tract calculi requires knowledge about ultrasound image capture, device manipulation, and interpretation. The purpose of this study was to validate a cognitive and technical skills curriculum to teach urologists ultrasonic propulsion to reposition kidney stones in tissue phantoms. Materials and Methods: Ten board-certified urologists recruited from a single institution underwent a didactic session on renal ultrasound imaging. Subjects completed technical skills modules in tissue phantoms, including kidney imaging, pushing a stone through a translucent maze, and repositioning a lower pole calyceal stone. Objective cognitive and technical performance metrics were recorded. Subjects completed a questionnaire to ascertain face and content validity on a five-point Likert scale. Results: Eight urologists (80%) had never attended a previous ultrasound course, and nine (90%) performed renal ultrasounds less frequently than every 6 months. Mean cognitive skills scores improved from 55% to 91% (p<0.0001) on pre- and post-didactic tests. In the kidney phantom, 10 subjects (100%) repositioned the lower pole calyceal stone to at least the lower pole infundibulum, while 9 (90%) successfully repositioned the stone to the renal pelvis. A mean±SD (15.7±13.3) pushes were required to complete the task over an average of 4.6±2.2 minutes. Urologists rated the curriculum's effectiveness and realism as a training tool at a mean score of 4.6/5.0 and 4.1/5.0, respectively. Conclusions: The curriculum for ultrasonic propulsion is effective and useful for training urologists with limited ultrasound proficiency in stone repositioning technique. Further studies in animate and human models will be required to assess predictive validity. PMID:24228719

Content and face validation of a curriculum for ultrasonic propulsion of calculi in a human renal model.

PubMed

Hsi, Ryan S; Dunmire, Barbrina; Cunitz, Bryan W; He, Xuemei; Sorensen, Mathew D; Harper, Jonathan D; Bailey, Michael R; Lendvay, Thomas S

2014-04-01

Ultrasonic propulsion to reposition urinary tract calculi requires knowledge about ultrasound image capture, device manipulation, and interpretation. The purpose of this study was to validate a cognitive and technical skills curriculum to teach urologists ultrasonic propulsion to reposition kidney stones in tissue phantoms. Ten board-certified urologists recruited from a single institution underwent a didactic session on renal ultrasound imaging. Subjects completed technical skills modules in tissue phantoms, including kidney imaging, pushing a stone through a translucent maze, and repositioning a lower pole calyceal stone. Objective cognitive and technical performance metrics were recorded. Subjects completed a questionnaire to ascertain face and content validity on a five-point Likert scale. Eight urologists (80%) had never attended a previous ultrasound course, and nine (90%) performed renal ultrasounds less frequently than every 6 months. Mean cognitive skills scores improved from 55% to 91% (p<0.0001) on pre- and post-didactic tests. In the kidney phantom, 10 subjects (100%) repositioned the lower pole calyceal stone to at least the lower pole infundibulum, while 9 (90%) successfully repositioned the stone to the renal pelvis. A mean±SD (15.7±13.3) pushes were required to complete the task over an average of 4.6±2.2 minutes. Urologists rated the curriculum's effectiveness and realism as a training tool at a mean score of 4.6/5.0 and 4.1/5.0, respectively. The curriculum for ultrasonic propulsion is effective and useful for training urologists with limited ultrasound proficiency in stone repositioning technique. Further studies in animate and human models will be required to assess predictive validity.

Repositioning the knee joint in human body FE models using a graphics-based technique.

PubMed

Jani, Dhaval; Chawla, Anoop; Mukherjee, Sudipto; Goyal, Rahul; Vusirikala, Nataraju; Jayaraman, Suresh

2012-01-01

Human body finite element models (FE-HBMs) are available in standard occupant or pedestrian postures. There is a need to have FE-HBMs in the same posture as a crash victim or to be configured in varying postures. Developing FE models for all possible positions is not practically viable. The current work aims at obtaining a posture-specific human lower extremity model by reconfiguring an existing one. A graphics-based technique was developed to reposition the lower extremity of an FE-HBM by specifying the flexion-extension angle. Elements of the model were segregated into rigid (bones) and deformable components (soft tissues). The bones were rotated about the flexion-extension axis followed by rotation about the longitudinal axis to capture the twisting of the tibia. The desired knee joint movement was thus achieved. Geometric heuristics were then used to reposition the skin. A mapping defined over the space between bones and the skin was used to regenerate the soft tissues. Mesh smoothing was then done to augment mesh quality. The developed method permits control over the kinematics of the joint and maintains the initial mesh quality of the model. For some critical areas (in the joint vicinity) where element distortion is large, mesh smoothing is done to improve mesh quality. A method to reposition the knee joint of a human body FE model was developed. Repositions of a model from 9 degrees of flexion to 90 degrees of flexion in just a few seconds without subjective interventions was demonstrated. Because the mesh quality of the repositioned model was maintained to a predefined level (typically to the level of a well-made model in the initial configuration), the model was suitable for subsequent simulations.

Deep Learning Applications for Predicting Pharmacological Properties of Drugs and Drug Repurposing Using Transcriptomic Data.

PubMed

Aliper, Alexander; Plis, Sergey; Artemov, Artem; Ulloa, Alvaro; Mamoshina, Polina; Zhavoronkov, Alex

2016-07-05

Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice and video recognition, robotics, and autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based on their transcriptional profiles. We used the perturbation samples of 678 drugs across A549, MCF-7, and PC-3 cell lines from the LINCS Project and linked those to 12 therapeutic use categories derived from MeSH. To train the DNN, we utilized both gene level transcriptomic data and transcriptomic data processed using a pathway activation scoring algorithm, for a pooled data set of samples perturbed with different concentrations of the drug for 6 and 24 hours. In both pathway and gene level classification, DNN achieved high classification accuracy and convincingly outperformed the support vector machine (SVM) model on every multiclass classification problem, however, models based on pathway level data performed significantly better. For the first time we demonstrate a deep learning neural net trained on transcriptomic data to recognize pharmacological properties of multiple drugs across different biological systems and conditions. We also propose using deep neural net confusion matrices for drug repositioning. This work is a proof of principle for applying deep learning to drug discovery and development.

Deep learning applications for predicting pharmacological properties of drugs and drug repurposing using transcriptomic data

PubMed Central

Aliper, Alexander; Plis, Sergey; Artemov, Artem; Ulloa, Alvaro; Mamoshina, Polina; Zhavoronkov, Alex

2016-01-01

Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice and video recognition, robotics and autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based on their transcriptional profiles. We used the perturbation samples of 678 drugs across A549, MCF‐7 and PC‐3 cell lines from the LINCS project and linked those to 12 therapeutic use categories derived from MeSH. To train the DNN, we utilized both gene level transcriptomic data and transcriptomic data processed using a pathway activation scoring algorithm, for a pooled dataset of samples perturbed with different concentrations of the drug for 6 and 24 hours. In both gene and pathway level classification, DNN convincingly outperformed support vector machine (SVM) model on every multiclass classification problem, however, models based on a pathway level classification perform better. For the first time we demonstrate a deep learning neural net trained on transcriptomic data to recognize pharmacological properties of multiple drugs across different biological systems and conditions. We also propose using deep neural net confusion matrices for drug repositioning. This work is a proof of principle for applying deep learning to drug discovery and development. PMID:27200455

SELF-BLM: Prediction of drug-target interactions via self-training SVM.

PubMed

Keum, Jongsoo; Nam, Hojung

2017-01-01

Predicting drug-target interactions is important for the development of novel drugs and the repositioning of drugs. To predict such interactions, there are a number of methods based on drug and target protein similarity. Although these methods, such as the bipartite local model (BLM), show promise, they often categorize unknown interactions as negative interaction. Therefore, these methods are not ideal for finding potential drug-target interactions that have not yet been validated as positive interactions. Thus, here we propose a method that integrates machine learning techniques, such as self-training support vector machine (SVM) and BLM, to develop a self-training bipartite local model (SELF-BLM) that facilitates the identification of potential interactions. The method first categorizes unlabeled interactions and negative interactions among unknown interactions using a clustering method. Then, using the BLM method and self-training SVM, the unlabeled interactions are self-trained and final local classification models are constructed. When applied to four classes of proteins that include enzymes, G-protein coupled receptors (GPCRs), ion channels, and nuclear receptors, SELF-BLM showed the best performance for predicting not only known interactions but also potential interactions in three protein classes compare to other related studies. The implemented software and supporting data are available at https://github.com/GIST-CSBL/SELF-BLM.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

PubMed

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian

2017-06-17

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. Copyright © 2017. Published by Elsevier Inc.

New drugs or alternative therapy to blurring the symptoms of fibromyalgia-a patent review.

PubMed

Oliveira, Marlange A; Guimarães, Adriana G; Araújo, Adriano A S; Quintans-Júnior, Lucindo J; Quintans, Jullyana S S

2017-10-01

Fibromyalgia (FM) is a musculoskeletal condition characterized by chronic widespread pain, tenderness and often accompanied by other comorbid conditions such as depression, anxiety, chronic fatigue, among others. Now, we aimed to survey the recent patents describing new drugs or alternative therapy for FM. Areas covered: This review covers the therapeutic patents published between 2010 and 2017 from specialized search databases (WIPO, DERWENT, INPI, ESPANET and USPTO) that report the discovery of new drugs or pharmacologic alternative for the treatment of FM. Expert opinion: New therapeutic substances have been proposed in the last seven years. At least as it has been found in our survey, most are still in the pre-clinical phase of the study, and its clinical applicability is unclear. However, other therapeutic approaches were found in patents such as well-established drugs in the market in combination or drug repositioning that combines the 'new analgesic' effects with the old side effects. Hence, it is a safe approach for pharmaceutical market, but poorer to patients who need a radical innovation. So, there is the emerging need for further studies on the safety and efficacy of such therapeutic measures and the search for improvement of side effects, as well as the development of new drugs that are unorthodox for different FM symptoms.

Analysis of intensity variability in multislice and cone beam computed tomography.

PubMed

Nackaerts, Olivia; Maes, Frederik; Yan, Hua; Couto Souza, Paulo; Pauwels, Ruben; Jacobs, Reinhilde

2011-08-01

The aim of this study was to evaluate the variability of intensity values in cone beam computed tomography (CBCT) imaging compared with multislice computed tomography Hounsfield units (MSCT HU) in order to assess the reliability of density assessments using CBCT images. A quality control phantom was scanned with an MSCT scanner and five CBCT scanners. In one CBCT scanner, the phantom was scanned repeatedly in the same and in different positions. Images were analyzed using registration to a mathematical model. MSCT images were used as a reference. Density profiles of MSCT showed stable HU values, whereas in CBCT imaging the intensity values were variable over the profile. Repositioning of the phantom resulted in large fluctuations in intensity values. The use of intensity values in CBCT images is not reliable, because the values are influenced by device, imaging parameters and positioning. © 2011 John Wiley & Sons A/S.

Patients' and sleeping partners' experience of treatment for sleep-related breathing disorders with a mandibular repositioning splint.

PubMed

Bates, C J; McDonald, J P

2006-01-28

To determine in detail the complications associated with the use of mandibular repositioning splints (MRS) to treat sleep-related breathing disorders. This prospective cross-sectional cohort study audits the management with mandibular repositioning splints of 121 patients suffering from sleep-related breathing disorders. Investigation of patients' and sleeping partners' perspectives on treatment was undertaken with the use of a questionnaire based study. Sixty-eight per cent of respondents reported that they were compliant with treatment; various side effects were reported of which excess salivation was the most common. Investigation of sleeping partners' perspectives revealed that 70% felt that their partners' snoring was improved and 47% felt that their partner's breathing pauses during sleep were reduced. Sixty-four per cent of the sleeping partners also reported that their own sleep pattern had improved since their partner's treatment. Mandibular repositioning splints used in the manner described by this paper are demonstrated to have a good compliance rate, provide successful treatment and exhibit only minor, reversible side effects.

Fusing literature and full network data improves disease similarity computation.

PubMed

Li, Ping; Nie, Yaling; Yu, Jingkai

2016-08-30

Identifying relatedness among diseases could help deepen understanding for the underlying pathogenic mechanisms of diseases, and facilitate drug repositioning projects. A number of methods for computing disease similarity had been developed; however, none of them were designed to utilize information of the entire protein interaction network, using instead only those interactions involving disease causing genes. Most of previously published methods required gene-disease association data, unfortunately, many diseases still have very few or no associated genes, which impeded broad adoption of those methods. In this study, we propose a new method (MedNetSim) for computing disease similarity by integrating medical literature and protein interaction network. MedNetSim consists of a network-based method (NetSim), which employs the entire protein interaction network, and a MEDLINE-based method (MedSim), which computes disease similarity by mining the biomedical literature. Among function-based methods, NetSim achieved the best performance. Its average AUC (area under the receiver operating characteristic curve) reached 95.2 %. MedSim, whose performance was even comparable to some function-based methods, acquired the highest average AUC in all semantic-based methods. Integration of MedSim and NetSim (MedNetSim) further improved the average AUC to 96.4 %. We further studied the effectiveness of different data sources. It was found that quality of protein interaction data was more important than its volume. On the contrary, higher volume of gene-disease association data was more beneficial, even with a lower reliability. Utilizing higher volume of disease-related gene data further improved the average AUC of MedNetSim and NetSim to 97.5 % and 96.7 %, respectively. Integrating biomedical literature and protein interaction network can be an effective way to compute disease similarity. Lacking sufficient disease-related gene data, literature-based methods such as MedSim can be a great addition to function-based algorithms. It may be beneficial to steer more resources torward studying gene-disease associations and improving the quality of protein interaction data. Disease similarities can be computed using the proposed methods at http:// www.digintelli.com:8000/ .

Cone-beam computed tomography fusion and navigation for real-time positron emission tomography-guided biopsies and ablations: a feasibility study.

PubMed

Abi-Jaoudeh, Nadine; Mielekamp, Peter; Noordhoek, Niels; Venkatesan, Aradhana M; Millo, Corina; Radaelli, Alessandro; Carelsen, Bart; Wood, Bradford J

2012-06-01

To describe a novel technique for multimodality positron emission tomography (PET) fusion-guided interventions that combines cone-beam computed tomography (CT) with PET/CT before the procedure. Subjects were selected among patients scheduled for a biopsy or ablation procedure. The lesions were not visible with conventional imaging methods or did not have uniform uptake on PET. Clinical success was defined by adequate histopathologic specimens for molecular profiling or diagnosis and by lack of enhancement on follow-up imaging for ablation procedures. Time to target (time elapsed between the completion of the initial cone-beam CT scan and first tissue sample or treatment), total procedure time (time from the moment the patient was on the table until the patient was off the table), and number of times the needle was repositioned were recorded. Seven patients underwent eight procedures (two ablations and six biopsies). Registration and procedures were completed successfully in all cases. Clinical success was achieved in all biopsy procedures and in one of the two ablation procedures. The needle was repositioned once in one biopsy procedure only. On average, the time to target was 38 minutes (range 13-54 min). Total procedure time was 95 minutes (range 51-240 min, which includes composite ablation). On average, fluoroscopy time was 2.5 minutes (range 1.3-6.2 min). An integrated cone-beam CT software platform can enable PET-guided biopsies and ablation procedures without the need for additional specialized hardware. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

PubMed Central

Sant'Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira-Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Rosário Almeida, Maria; Reixach, Natàlia; Insa, Raul; Velazquez-Campoy, Adrian; Reverter, David; Reig, Núria; Ventura, Salvador

2016-01-01

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. PMID:26902880

Repositioning Ideology Critique in a Critical Theory of Adult Learning.

ERIC Educational Resources Information Center

Brookfield, Stephen

2001-01-01

Reexamines critical theory as a response to Marxism and repositions ideology critique as a crucial adult learning process. Argues that a critical theory of adult learning should focus on how adults learn to recognize and challenge ideological domination and manipulation. (Contains 31 references.) (SK)

Reproducibility of a peripheral quantitative computed tomography scan protocol to measure the material properties of the second metatarsal.

PubMed

Chaplais, Elodie; Greene, David; Hood, Anita; Telfer, Scott; du Toit, Verona; Singh-Grewal, Davinder; Burns, Joshua; Rome, Keith; Schiferl, Daniel J; Hendry, Gordon J

2014-07-19

Peripheral quantitative computed tomography (pQCT) is an established technology that allows for the measurement of the material properties of bone. Alterations to bone architecture are associated with an increased risk of fracture. Further pQCT research is necessary to identify regions of interest that are prone to fracture risk in people with chronic diseases. The second metatarsal is a common site for the development of insufficiency fractures, and as such the aim of this study was to assess the reproducibility of a novel scanning protocol of the second metatarsal using pQCT. Eleven embalmed cadaveric leg specimens were scanned six times; three times with and without repositioning. Each foot was positioned on a custom-designed acrylic foot plate to permit unimpeded scans of the region of interest. Sixty-six scans were obtained at 15% (distal) and 50% (mid shaft) of the second metatarsal. Voxel size and scan speed were reduced to 0.40 mm and 25 mm.sec(-1). The reference line was positioned at the most distal portion of the 2(nd) metatarsal. Repeated measurements of six key variables related to bone properties were subject to reproducibility testing. Data were log transformed and reproducibility of scans were assessed using intraclass correlation coefficients (ICC) and coefficients of variation (CV%). Reproducibility of the measurements without repositioning were estimated as: trabecular area (ICC 0.95; CV% 2.4), trabecular density (ICC 0.98; CV% 3.0), Strength Strain Index (SSI) - distal (ICC 0.99; CV% 5.6), cortical area (ICC 1.0; CV% 1.5), cortical density (ICC 0.99; CV% 0.1), SSI - mid shaft (ICC 1.0; CV% 2.4). Reproducibility of the measurements after repositioning were estimated as: trabecular area (ICC 0.96; CV% 2.4), trabecular density (ICC 0.98; CV% 2.8), SSI - distal (ICC 1.0; CV% 3.5), cortical area (ICC 0.99; CV%2.4), cortical density (ICC 0.98; CV% 0.8), SSI - mid shaft (ICC 0.99; CV% 3.2). The scanning protocol generated excellent reproducibility for key bone properties measured at the distal and mid-shaft regions of the 2(nd) metatarsal. This protocol extends the capabilities of pQCT to evaluate bone quality in people who may be at an increased risk of metatarsal insufficiency fractures.

Reproducibility of a peripheral quantitative computed tomography scan protocol to measure the material properties of the second metatarsal

PubMed Central

2014-01-01

Background Peripheral quantitative computed tomography (pQCT) is an established technology that allows for the measurement of the material properties of bone. Alterations to bone architecture are associated with an increased risk of fracture. Further pQCT research is necessary to identify regions of interest that are prone to fracture risk in people with chronic diseases. The second metatarsal is a common site for the development of insufficiency fractures, and as such the aim of this study was to assess the reproducibility of a novel scanning protocol of the second metatarsal using pQCT. Methods Eleven embalmed cadaveric leg specimens were scanned six times; three times with and without repositioning. Each foot was positioned on a custom-designed acrylic foot plate to permit unimpeded scans of the region of interest. Sixty-six scans were obtained at 15% (distal) and 50% (mid shaft) of the second metatarsal. Voxel size and scan speed were reduced to 0.40 mm and 25 mm.sec-1. The reference line was positioned at the most distal portion of the 2nd metatarsal. Repeated measurements of six key variables related to bone properties were subject to reproducibility testing. Data were log transformed and reproducibility of scans were assessed using intraclass correlation coefficients (ICC) and coefficients of variation (CV%). Results Reproducibility of the measurements without repositioning were estimated as: trabecular area (ICC 0.95; CV% 2.4), trabecular density (ICC 0.98; CV% 3.0), Strength Strain Index (SSI) - distal (ICC 0.99; CV% 5.6), cortical area (ICC 1.0; CV% 1.5), cortical density (ICC 0.99; CV% 0.1), SSI – mid shaft (ICC 1.0; CV% 2.4). Reproducibility of the measurements after repositioning were estimated as: trabecular area (ICC 0.96; CV% 2.4), trabecular density (ICC 0.98; CV% 2.8), SSI - distal (ICC 1.0; CV% 3.5), cortical area (ICC 0.99; CV%2.4), cortical density (ICC 0.98; CV% 0.8), SSI – mid shaft (ICC 0.99; CV% 3.2). Conclusions The scanning protocol generated excellent reproducibility for key bone properties measured at the distal and mid-shaft regions of the 2nd metatarsal. This protocol extends the capabilities of pQCT to evaluate bone quality in people who may be at an increased risk of metatarsal insufficiency fractures. PMID:25037451

A repositionable valved stent for endovascular treatment of deteriorated bioprostheses.

PubMed

Zegdi, Rachid; Khabbaz, Ziad; Borenstein, Nicolas; Fabiani, Jean-Noël

2006-10-03

We report our animal experience of endovascular valve replacement (VR) of failed bioprosthesis (BP) using an original delivery catheter allowing repositioning of the valved stent (VS). Among the different devices designed for percutaneous VR, none has the potential for repositioning of a fully deployed VS. Five sheep underwent, on beating heart, tricuspid VR with a stented BP. Prolapse of 1 leaflet was induced by tearing. For the endovascular tricuspid VR, we used a VS constructed with a nitinol self-expandable stent and a porcine stentless aortic valve. We also used an original delivery catheter, allowing repositioning of the VS through a compression or relaxation mechanism of the stent. Epicardial echocardiography and right ventriculography showed severe tricuspid regurgitation, with a regurgitant jet extending to the inferior vena cava. After surgical exposure to the infrarenal inferior vena cava, the VS was successfully implanted inside the failed BP in all cases. Repositioning of the fully deployed VS was always possible. Echocardiographic and macroscopic studies revealed adequate VS positioning, excellent leaflet opening, and absence of any intraprosthetic or periprosthetic leak. Endovascular VR was easily performed in sheep with failed BP in the tricuspid position. The novel delivery catheter allowed adequate repositioning of our fully deployed VS before its definitive release. One may anticipate that the safety improvement conferred by this new technology will certainly favor the development of percutaneous VR in clinical practice.

Modified Lip Repositioning with Esthetic Crown Lengthening: A Combined Approach to Treating Excessive Gingival Display.

PubMed

Sánchez, Isis M; Gaud-Quintana, Sadja; Stern, Jacob K

Lip repositioning surgery to address excessive gingival display induced by different etiologies has received major attention recently. Several techniques and variations have been reported, including myotomy or repositioning of the levator labii superioris muscle, Le Fort impaction, maxillary gingivectomies, botulinum toxin injections, and lip stabilization. This study reports a case of excessive gingival display treated by a modified combined approach. A 25-year-old woman with a 4- to 8-mm gingival display when smiling caused by a combination of short clinical crowns induced by an altered passive eruption and hypermobility of the upper lip underwent a staged esthetic crown-lengthening procedure followed by a modified lip repositioning technique. A description of the technique and a comparison with other modes of therapy is discussed. This modified approach for treating the hypermobile lip included a bilateral removal of a partial-thickness strip of mucosa from the maxillary buccal vestibule without severing the muscle, leaving the midline frenum intact and suturing the lip mucosa to the mucogingival line. The narrower vestibule and increased tooth length resulted in a symmetric and pleasing gingival display when smiling that remained stable over time. With proper diagnosis and sequence of therapy, modified lip repositioning surgery combined with esthetic crown lengthening can be used predictably to treat excessive gingival display and enhance smile esthetics.

Influence of prolonged unilateral cervical muscle contraction on head repositioning--decreased overshoot after a 5-min static muscle contraction task.

PubMed

Malmström, Eva-Maj; Karlberg, Mikael; Holmström, Eva; Fransson, Per-Anders; Hansson, Gert-Ake; Magnusson, Måns

2010-06-01

The ability to reproduce a specified head-on-trunk position can be an indirect test of cervical proprioception. This ability is affected in subjects with neck pain, but it is unclear whether and how much pain or continuous muscle contraction factors contribute to this effect. We studied the influence of a static unilateral neck muscle contraction task (5 min of lateral flexion at 30% of maximal voluntary contraction) on head repositioning ability in 20 subjects (10 women, 10 men; mean age 37 years) with healthy necks. Head repositioning ability was tested in the horizontal plane with 30 degrees target and neutral head position tests; head position was recorded by Zebris((R)), an ultrasound-based motion analyser. Head repositioning ability was analysed for accuracy (mean of signed differences between introduced and reproduced positions) and precision (standard deviation of the differences). Accuracy of head repositioning ability increased significantly after the muscle contraction task, as the normal overshoot was reduced. An average overshoot of 7.1 degrees decreased to 4.6 degrees after the muscle contraction task for the 30 degrees target and from 2.2 degrees to 1.4 degrees for neutral head position. The increased accuracy was most pronounced for movements directed towards the activated side. Hence, prolonged unilateral neck muscle contraction may increase the sensitivity of cervical proprioceptors.

Sir Sandford Fleming College Repositioning Strategies Report.

ERIC Educational Resources Information Center

Sir Sandford Fleming Coll., Peterborough (Ontario).

This report describes repositioning strategies undertaken by Sir Sandford Fleming College, in Ontario, to respond to changing student demographics, educational demands, and reduced funding. Following opening remarks by the college president providing an overview of the strategies and the use of all-staff meetings to generate responses from the…

[Management of disk displacement with condylar fracture].

PubMed

Yu, Shi-bin; Li, Zu-bing; Yang, Xue-wen; Zhao, Ji-hong; Dong, Yao-jun

2003-07-01

To investigate clinical features of disk displacement during the course of condylar fracture and to explore the techniques of disk reposition and suturation. 32 patients (10 females and 22 males) who had disk displacements with condylar fractures were followed up. Reduction and reposition of the dislocated disks simultaneously with fixation of fractures were performed. 7 patients underwent intermaxillary fixation with elastic bands for 1 to 2 weeks. The occlusions were satisfactory in all cases but one for the reason of ramus height loss. No TMJ symptom was found when examined 3 months post operation. Anterior disk displacements were most occurred with high condylar process fractures. Surgical reposition and suturation of disk play an important role for the later TMJ-function.

Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key.

PubMed

Haupt, V Joachim; Daminelli, Simone; Schroeder, Michael

2013-01-01

Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence.

Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors.

PubMed

Choi, Joonhyeok; Jee, Jun-Goo

2015-12-02

Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: The hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) and the oxidation of DOPA to dopaquinone. Developing functional modulators of tyrosinase is important for therapeutic and cosmetic purposes. Given the abundance of thiourea moiety in known tyrosinase inhibitors, we studied other thiourea-containing drugs as potential tyrosinase inhibitors. The thiourea-containing drugs in clinical use were retrieved and tested for their ability to inhibit tyrosinase. We observed that methimazole, thiouracil, methylthiouracil, propylthiouracil, ambazone, and thioacetazone inhibited mushroom tyrosinase. Except for methimazole, there was limited information regarding the activity of other drugs against tyrosinase. Both thioacetazone and ambazone significantly inhibited tyrosinase, with IC50 of 14 and 15 μM, respectively. Ambazone decreased melanin content without causing cellular toxicity at 20 μM in B16F10 cells. The activity of ambazone was stronger than that of kojic acid both in enzyme and melanin content assays. Kinetics of enzyme inhibition assigned the thiourea-containg drugs as non-competitive inhibitors. The complex models by docking simulation suggested that the intermolecular hydrogen bond via the nitrogen of thiourea and the contacts via thione were equally important for interacting with tyrosinase. These data were consistent with the results of enzyme assays with the analogues of thiourea.

Computation, prediction, and experimental tests of fitness for bacteriophage T7 mutants with permuted genomes

NASA Astrophysics Data System (ADS)

Endy, Drew; You, Lingchong; Yin, John; Molineux, Ian J.

2000-05-01

We created a simulation based on experimental data from bacteriophage T7 that computes the developmental cycle of the wild-type phage and also of mutants that have an altered genome order. We used the simulation to compute the fitness of more than 105 mutants. We tested these computations by constructing and experimentally characterizing T7 mutants in which we repositioned gene 1, coding for T7 RNA polymerase. Computed protein synthesis rates for ectopic gene 1 strains were in moderate agreement with observed rates. Computed phage-doubling rates were close to observations for two of four strains, but significantly overestimated those of the other two. Computations indicate that the genome organization of wild-type T7 is nearly optimal for growth: only 2.8% of random genome permutations were computed to grow faster, the highest 31% faster, than wild type. Specific discrepancies between computations and observations suggest that a better understanding of the translation efficiency of individual mRNAs and the functions of qualitatively "nonessential" genes will be needed to improve the T7 simulation. In silico representations of biological systems can serve to assess and advance our understanding of the underlying biology. Iteration between computation, prediction, and observation should increase the rate at which biological hypotheses are formulated and tested.

76 FR 6488 - Notice of Submission of Proposed Information Collection to OMB Conversion of Efficiency Units to...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-04

... and Budget (OMB) for review, as required by the Paperwork Reduction Act. The Department is soliciting... and results in the long- term financial and physical repositioning of the project. DATES: Comments Due...-term financial and physical repositioning of the project. Frequency of Submission: On-occasion...

Closed Circuit? Flow, Influence and the Liquid Management of Learning and Skills

ERIC Educational Resources Information Center

Beighton, Christian

2017-01-01

A new discourse is being deployed by the English learning and skills sector's new professional body, the Education and Training Foundation (ETF). This discourse repositions learning within a specific vision of corporate expectations. With a focus on deregulation in the sector and employer engagement, this repositioning deploys the terminology and…

On the Shoulders of Giants? Global Science, Resource Asymmetries, and Repositioning of Research Universities in China and Russia

ERIC Educational Resources Information Center

Oleksiyenko, Anatoly

2014-01-01

Chinese and Russian universities are increasingly drawn into center-periphery repositioning, as they compete for symbolic, financial, and intellectual resources locally and globally. However, their strategies on national and institutional linkages differ with regards to the individual scientist's powers in knowledge production. As global…

Repositioning Guidance and Counselling and Curriculum Innovation in Higher Education in Nigeria

ERIC Educational Resources Information Center

Onyilofor, Florence N. C.

2013-01-01

This study focuses on repositioning guidance and counseling and curriculum innovation in higher education in Nigeria. Descriptive survey research design was employed in the study. The study covered four Federal universities in the South-West Geopolitical zone of Nigeria, namely University of Ibadan in Oyo State; Obafemi Awolowo University, Ile-Ife…

Transposition of the paraclival carotid artery: a novel concept of self-retaining vascular retraction during endoscopic endonasal skull base surgery technical report.

PubMed

Freeman, Jacob L; Sampath, Raghuram; Casey, Michael A; Quattlebaum, Steven Craig; Ramakrishnan, Vijay R; Youssef, A Samy

2016-08-01

Fixed retraction of the internal carotid artery (ICA) has previously been described for use during transcranial microscopic surgery. We report the novel use of a self-retaining microvascular retractor for static repositioning and protection of the ICA during expanded endonasal endoscopic approaches to the paramedian skull base. The transmaxillary, transpterygoid approach was performed in five cadaver heads (ten sides). The self-retaining microvascular retractor was used to laterally reposition the pterygopalatine fossa contents during exposure of the pterygoid base/plates and the paraclival ICA to expose the petrous apex. Maximum ICA retraction distance was measured in the x-axis for all ten sides. The average horizontal distance of ICA retraction measured at the mid-paraclival segment for all ten sides was 4.75 mm. In all cases, the carotid artery was repositioned without injury to the vessel or disruption of the surrounding neurovascular structures. Static repositioning of the ICA and other delicate neurovascular structures was effectively performed during endonasal, endoscopic cadaveric surgery of the skull base and has potential merits in live patients.

Place of the reposition flap in the treatment of distal amputations of the fingers.

PubMed

Sbai, Mohamed Ali; M'chirgui, Mayssa El; Maalla, Riadh; Khorbi, Adel

2017-08-01

Distal finger amputations pose a therapeutic problem with the distal fragment quality. Reimplantation remains the reference treatment for functional and aesthetic recovery of the hand. The interest of this study is to propose the reposition flap as an alternative to different hedging techniques in the proximal stump, in many situations where revascularization is impossible. It consists in osteosynthesis of the bone fragment and its coverage by a pedicled local flap. The technique of reposition flap was evaluated retrospectively between 2003 and 2016 through a study of 13 patients compiled in Nabeul orthopedic department. For each patient, the sensitivity, the pulp trophicity, the interphalangeal mobility, the digital length, the appearance of the nail and radiological consolidation were evaluated. The reposition flap keeps more than 80% of the length of p3. This procedure improves nail aesthetics in comparison with the regularizations. There is no significant difference in sensitivity of the pulp or of the mobility of the distal inter-phalangeal (DIP) joint as a function of the technique studied. However there is a significant difference in average test of the Quick Dash (350 against 500 for regularizations). The reposition flap seems to be a good alternative to regularization in the context of trans-p3 fingers amputations, in which the distal fragment is not revascularizable. It allows better aesthetic and functional results. Copyright © 2017 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Vertical repositioning accuracy of magnetic mounting systems on 4 articulator models.

PubMed

Lee, Wonsup; Kwon, Ho-Beom

2018-03-01

Research of the ability of a cast mounted on an articulator on maintaining the identical position of a cast mounted on an articulator after repeated repositioning is lacking, despite the possible effects this may have on the occlusion of a mounted cast. The purpose of this in vitro study was to verify and compare the vertical repositioning accuracy of 4 different, commercially available articulator magnetic mounting plate systems. Four articulators and their associated magnetic mounting plates were selected for the study. These were the Artex AR articulator (Amann Girrbach AG), the Denar Mark II articulator (Whip Mix Corp), the Kavo Protar Evo articulator (Kavo Dental GmbH), and the SAM3 articulator (SAM Präzisionstechnik GmbH). Three new magnetic mounting plates were prepared for each articulator system. The repositioning accuracy of each mounting plate was evaluated by comparing the standard deviation of the vertical distances measured between the mounting plate and a laser displacement sensor. The lower arm of the articulator was secured, and the vertical distance was measured by positioning the laser displacement sensor positioned vertically above the mounting plate. Once the vertical distance was measured, the mounting plate was detached from the articulator and reattached manually to prepare for the next measurement. This procedure was repeated 30 times for each of the 3 magnetic mounting plates. Data were analyzed by ANOVA for 2-stage nested design and the Levene test (α=.05). Significant differences were detected among articulator systems and between magnetic mounting plates of the same type. The standard deviations of the measurements made with the Artex AR articulator, Denar Mark II articulator, Kavo Protar Evo articulator, and SAM3 articulator were 0.0027, 0.0308, 0.0214, and 0.0215 mm, respectively. Thus, the repositioning accuracy could be ranked in the order as follows: Artex AR, Kavo Protar Evo, SAM3, and Denar Mark II. The position of the magnetic mounting plate after repositioning did not maintain an identical position in the vertical dimension on any of the 4 articulator models tested. The repositioning accuracy of the mounting plates showed significant differences among the articulators tested in this study. Copyright © 2017 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

BRCA-Monet: a breast cancer specific drug treatment mode-of-action network for treatment effective prediction using large scale microarray database.

PubMed

Ma, Chifeng; Chen, Hung-I; Flores, Mario; Huang, Yufei; Chen, Yidong

2013-01-01

Connectivity map (cMap) is a recent developed dataset and algorithm for uncovering and understanding the treatment effect of small molecules on different cancer cell lines. It is widely used but there are still remaining challenges for accurate predictions. Here, we propose BRCA-MoNet, a network of drug mode of action (MoA) specific to breast cancer, which is constructed based on the cMap dataset. A drug signature selection algorithm fitting the characteristic of cMap data, a quality control scheme as well as a novel query algorithm based on BRCA-MoNet are developed for more effective prediction of drug effects. BRCA-MoNet was applied to three independent data sets obtained from the GEO database: Estrodial treated MCF7 cell line, BMS-754807 treated MCF7 cell line, and a breast cancer patient microarray dataset. In the first case, BRCA-MoNet could identify drug MoAs likely to share same and reverse treatment effect. In the second case, the result demonstrated the potential of BRCA-MoNet to reposition drugs and predict treatment effects for drugs not in cMap data. In the third case, a possible procedure of personalized drug selection is showcased. The results clearly demonstrated that the proposed BRCA-MoNet approach can provide increased prediction power to cMap and thus will be useful for identification of new therapeutic candidates.

Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents.

PubMed

Kang, Seokmin; Lee, Jung Moo; Jeon, Borami; Elkamhawy, Ahmed; Paik, Sora; Hong, Jinpyo; Oh, Soo-Jin; Paek, Sun Ha; Lee, C Justin; Hassan, Ahmed H E; Kang, Sang Soo; Roh, Eun Joo

2018-05-10

Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4-5 times more potent inhibitory activity than trifluoperazine with IC 50  = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC 50  = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca 2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Color group selection for computer interfaces

NASA Astrophysics Data System (ADS)

Lyons, Paul; Moretti, Giovanni; Wilson, Mark

2000-06-01

We describe a low-impact method for coloring interfaces harmoniously. The method uses a model that characterizes the overall image including the need for distinguishability between interface components. The degree of visual distinction between one component and other components, and its color strength (which increases with its importance and decreases with its size and longevity), are used in generating a rigid ball-and-stick 'color molecule,' which represents the color relationships between the interface components. The shape of the color molecule is chosen to conform to standard principles of color harmony (like colors harmonize, complementary colors harmonize, cycles in the color space harmonize, and so on). The color molecule's shape is fixed, but its position and orientation within the perceptually uniform color solid are not. The end user of the application chooses a new color scheme for the complete interface by repositioning the molecule within the color space. The molecule's shape and rigidity, and the space's perceptual uniformity, ensures the distinguishability and color harmony of the components are maintained. The system produces a selection of color schemes which often include subtle 'nameless' colors that people rarely choose using conventional color controls, but which blend smoothly into a harmonious color scheme. A new set of equally harmonious color schemes only requires repositioning the color molecule within the space.

Laryngeal dislocation after ventral fusion of the cervical spine

PubMed Central

Krauel, Jenny; Winkler, Dietrich; Münscher, Adrian; Tank, Sascha

2013-01-01

We report on a 70-year-old patient who underwent ventral fusion of the cervical spine (C3/4 and C4/5) for spinal canal stenosis performed by the neurosurgery department. The patient suffered an exceedingly rare complication of the surgery – laryngeal dislocation. Had the deformed laryngeal structures been overlooked and the patient extubated as usual after surgery, reintubation would have been impossible due to the associated swelling, which might have had disastrous consequences. Leftward dislocation of the larynx became apparent post-operatively, but prior to extubation. Extubation was therefore postponed and a subsequent computed tomography (CT) scan revealed entrapment of laryngeal structures within the osteosynthesis. A trial of repositioning using microlaryngoscopy performed by otolaryngology (ears, nose and throat) specialists failed, making open surgical revision necessary. At surgery, the entrapped laryngeal tissue was successfully mobilised. Laryngeal oedema developed despite prompt repositioning; thus, necessitating tracheotomy and long-term ventilation. Laryngeal dislocation may be an unusual cause of post-operative neck swelling after anterior cervical spine surgery and should be considered in the differential diagnosis if surgical site haematoma and other causes have been ruled out. Imaging studies including CT of the neck may be needed before extubation to confirm the suspicion and should be promptly obtained to facilitate specific treatment. PMID:23983289

A new approach of splint-less orthognathic surgery using a personalized orthognathic surgical guide system: A preliminary study

PubMed Central

Li, B.; Shen, S.; Jiang, W.; Li, J.; Jiang, T.; Xia, J. J.; Shen, S. G.; Wang, X.

2017-01-01

The purpose of this study was to evaluate a personalized orthognathic surgical guide (POSG) system for bimaxillary surgery without the use of surgical splint. Ten patients with dentofacial deformities were enrolled. Surgeries were planned with the computer-aided surgical simulation method. The POSG system was designed for both maxillary and mandibular surgery. Each consisted of cutting guides and three-dimensionally (3D) printed custom titanium plates to guide the osteotomy and repositioning the bony segments without the use of the surgical splints. Finally, the outcome evaluation was completed by comparing planned outcomes with postoperative outcomes. All operations were successfully completed using the POSG system. The largest root-mean-square deviations were 0.74 mm and 1.93° for the maxillary dental arch, 1.10 mm and 2.82° for the mandibular arch, 0.83 mm and 2.59° for the mandibular body, and 0.98 mm and 2.45° for the proximal segments. The results of the study indicated that our POSG system is capable of accurately and effectively transferring the surgical plan without the use of surgical splint. A significant advantage is that the repositioning of the bony segments is independent to the mandibular autorotation, thus eliminates the potential problems associated with the surgical splint. PMID:28552440

Combined online and offline adaptive radiation therapy: a dosimetric feasibility study.

PubMed

Yang, Chengliang; Liu, Feng; Ahunbay, Ergun; Chang, Yu-Wen; Lawton, Colleen; Schultz, Christopher; Wang, Dian; Firat, Selim; Erickson, Beth; Li, X Allen

2014-01-01

The purpose of this work is to explore a new adaptive radiation therapy (ART) strategy, combined "online and offline" ART, that can fully account for interfraction variations similar to the existing online ART but with substantially reduced online effort. The concept for the combined ART is to perform online ART only for the fractions with obvious interfraction variations and to deliver the ART plan for that online fraction as well as the subsequent fractions until the next online fraction needs to be adapted. To demonstrate the idea, the daily computed tomographic (CT) data acquired during image guided radiation therapy (IGRT) with an in-room CT (CTVision, Siemens Healthcare, Amarillo, TX) for 6 representative patients (including 2 prostate, 1 head-and-neck, and 1 pancreatic cancer, 1 adrenal carcinoma, and 1 craniopharyngioma patients) were analyzed. Three types of plans were generated based on the following selected daily CTs: (1) IGRT repositioning plan, generated by applying the repositioning shifts to the original plan (representing the current IGRT practice); (2) Re-Opt plan, generated with full-scope optimization; and (3) ART plan, either online ART plan generated with an online ART tool (RealArt, Prowess Inc, Concord, CA) or offline ART plan generated with shifts from the online ART plan. Various dose-volume parameters were compared with measure dosimetric benefits of the ART plans based on daily dose distributions and the cumulative dose maps obtained with deformable image registration. In general, for all the cases studied, the ART (with 3-5 online ART) and Re-Opt plans provide comparable plan quality and offer significantly better target coverage and normal tissue sparing when compared with the repositioning plans. This improvement is statistically significant. The combined online and offline ART is dosimetrically equivalent to the online ART but with substantially reduced online effort, and enables immediate delivery of the adaptive plan when an obvious anatomic change is observed. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

PubMed Central

Tonge, Peter J.; Xie, Lei; Bourne, Philip E.

2009-01-01

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs. PMID:19578428

Learner Engagement under the "Regulatory Gaze": Possibilities for Re-Positioning Early Childhood Pre-Service Teachers as Autonomous Professionals

ERIC Educational Resources Information Center

Jovanovic, Jessie; Fane, Jennifer

2016-01-01

In a climate of increasing regulation within early childhood education and care services, and the greater re-positioning of professionals within public sectors, this article seeks to extend the literature surrounding risk and regulation in early childhood. In efforts to "push back" against the "regulatory gaze" in the early…

(Re)Positioning Team Teaching: The Visibility and Viability of Learning in Classrooms

ERIC Educational Resources Information Center

Ó Murchú, Finn; Conway, Paul

2017-01-01

Team teaching, where two teachers teach in the same classroom at the same time, while not a new concept, is increasingly being positioned and repositioned in research and policy literatures as central in advancing a range of valued educational goals. These goals include supporting inclusive learning for all students as well as supporting…

Repositioning Your EMBA Program and Reinventing Your Brand: A Case Study Analysis

ERIC Educational Resources Information Center

Petit, Francis

2009-01-01

The purpose of this research is to illustrate how Fordham University, the Jesuit University of New York, repositioned its Executive MBA Program and reinvented its brand, over a ten year period. More specifically, this research will analyze the current state of the Executive MBA market and will discuss the best practices and frameworks implemented…

Repositioning Technical and Vocational Education and Training (TVET) for Youths Employment and National Security in Nigeria

ERIC Educational Resources Information Center

Ogbunaya, T. C.; Udoudo, Ekereobong S.

2015-01-01

The paper focused on repositioning Technical and Vocational Education and Training (TVET) for youth's employment and national security in Nigeria. It examined briefly the concepts of technical vocational education and training (TVET), youths, unemployment and national security as well as the effects of unemployment on national security in Nigeria.…

Challenges and recommendations for obtaining chemical structures of industry-provided repurposing candidates.

PubMed

Southan, Christopher; Williams, Antony J; Ekins, Sean

2013-01-01

There is an expanding amount of interest directed at the repurposing and repositioning of drugs, as well as how in silico methods can assist these endeavors. Recent repurposing project tendering calls by the National Center for Advancing Translational Sciences (USA) and the Medical Research Council (UK) have included compound information and pharmacological data. However, none of the internal company development code names were assigned to chemical structures in the official documentation. This not only abrogates in silico analysis to support repurposing but consequently necessitates data gathering and curation to assign structures. Here, we describe the approaches, results and major challenges associated with this. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protein nanoparticles are nontoxic, tuneable cell stressors.

PubMed

de Pinho Favaro, Marianna Teixeira; Sánchez-García, Laura; Sánchez-Chardi, Alejandro; Roldán, Mónica; Unzueta, Ugutz; Serna, Naroa; Cano-Garrido, Olivia; Azzoni, Adriano Rodrigues; Ferrer-Miralles, Neus; Villaverde, Antonio; Vázquez, Esther

2018-02-01

Nanoparticle-cell interactions can promote cell toxicity and stimulate particular behavioral patterns, but cell responses to protein nanomaterials have been poorly studied. By repositioning oligomerization domains in a simple, modular self-assembling protein platform, we have generated closely related but distinguishable homomeric nanoparticles. Composed by building blocks with modular domains arranged in different order, they share amino acid composition. These materials, once exposed to cultured cells, are differentially internalized in absence of toxicity and trigger distinctive cell adaptive responses, monitored by the emission of tubular filopodia and enhanced drug sensitivity. The capability to rapidly modulate such cell responses by conventional protein engineering reveals protein nanoparticles as tuneable, versatile and potent cell stressors for cell-targeted conditioning.

Repositioning the Patient:

PubMed Central

Mold, Alex

2013-01-01

Summary This article explores how and why the patient came to be repositioned as a political actor within British health care during the 1960s and 1970s. Focusing on the role played by patient organizations, it is suggested that the repositioning of the patient needs to be seen in the light of growing demands for greater patient autonomy and the application of consumerist principles to health. Examining the activities of two patient groups—the National Association for the Welfare of Children in Hospital (NAWCH) and the Patients Association (PA)—indicates that while such groups undoubtedly placed more emphasis on individual autonomy, collective concerns did not entirely fall away. The voices of patients, as well as the patient, continued to matter within British health care. PMID:23811711

Astigmatism and Refractive Outcome After Late In-The-Bag Intraocular Lens Dislocation Surgery: A Randomized Clinical Trial.

PubMed

Kristianslund, Olav; Østern, Atle Einar; Drolsum, Liv

2017-09-01

To compare surgically induced astigmatism (SIA) and refractive outcomes between two operation methods for late in-the-bag IOL dislocation. In this prospective, randomized, parallel-group clinical trial, 104 patients (eyes) were assigned to IOL repositioning by scleral suturing 1.5- to 2-mm posterior to limbus (n = 54) or IOL exchange with a retropupillar iris-claw IOL using a 5.5-mm scleral pocket incision (n = 50). The SIA was determined by vector analysis through conversion of corneal cylinders to Cartesian coordinates, and is presented as magnitude in diopters @ direction in degrees (D @ °). Follow-up was 6 months. The SIA was 0.24 D @ 8° for IOL repositioning and 0.65 D @ 171° for IOL exchange, which was a nonsignificant group difference (X coordinate: P = 0.08; Y coordinate: P = 0.16). Mean SIA magnitude was 0.60 ± 0.50 D and 1.12 ± 0.85 D, respectively (P < 0.001). Mean postoperative spherical equivalent was -1.6 ± 1.6 D after IOL repositioning and -0.5 ± 1.0 D after IOL exchange (P < 0.001). For IOL repositioning, this represented a mean myopic shift of -0.7 ± 1.1 D compared with before the IOL dislocation (P < 0.001). For IOL exchange, it was within ±1 D of target refraction in 83% of the patients. Surgically induced astigmatism was modest in both operation groups, albeit with a tendency of being more pronounced for IOL exchange. Repositioning surgery led to a myopic shift, whereas exchange surgery provided good refractive predictability.

Drug repurposing for the treatment of glioblastoma multiforme.

PubMed

Abbruzzese, Claudia; Matteoni, Silvia; Signore, Michele; Cardone, Luca; Nath, Kavindra; Glickson, Jerry D; Paggi, Marco G

2017-11-28

Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide. Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types. The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.

Beyond "the West as Method": Repositioning the Japanese Education Research Communities in/against the Global Structure of Academic Knowledge

ERIC Educational Resources Information Center

Takayama, Keita

2016-01-01

Drawing on the recent critiques of the global knowledge economy of social science research, this article explores possible ways in which the Japanese education research communities can reposition themselves in the wider international education research community. The premises of this discussion are that there exists a global structure of academic…

The comparison of cervical repositioning errors according to smartphone addiction grades.

PubMed

Lee, Jeonhyeong; Seo, Kyochul

2014-04-01

[Purpose] The purpose of this study was to compare cervical repositioning errors according to smartphone addiction grades of adults in their 20s. [Subjects and Methods] A survey of smartphone addiction was conducted of 200 adults. Based on the survey results, 30 subjects were chosen to participate in this study, and they were divided into three groups of 10; a Normal Group, a Moderate Addiction Group, and a Severe Addiction Group. After attaching a C-ROM, we measured the cervical repositioning errors of flexion, extension, right lateral flexion and left lateral flexion. [Results] Significant differences in the cervical repositioning errors of flexion, extension, and right and left lateral flexion were found among the Normal Group, Moderate Addiction Group, and Severe Addiction Group. In particular, the Severe Addiction Group showed the largest errors. [Conclusion] The result indicates that as smartphone addiction becomes more severe, a person is more likely to show impaired proprioception, as well as impaired ability to recognize the right posture. Thus, musculoskeletal problems due to smartphone addiction should be resolved through social cognition and intervention, and physical therapeutic education and intervention to educate people about correct postures.

Changes in temporomandibular joint spaces after arthroscopic disc repositioning: a self-control study

PubMed Central

Kai Hu, Ying; Abdelrehem, Ahmed; Yang, Chi; Cai, Xie Yi; Xie, Qian Yang; Sah, Manoj Kumar

2017-01-01

Disc repositioning is a common procedure for patients with anterior disc displacement (ADD). The purpose of this retrospective record-based study was to evaluate changes in the widths of joint spaces and condylar position changes in patients with unilateral ADD following arthroscopic disc repositioning, with the healthy sides as self-control, using magnetic resonance images (MRI).Widths of anterior, superior, and posterior joint spaces (AS, SS, and PS) were measured. The condylar position was described as anterior, centric or posterior, expressed as . Paired-t test and Chi-square test were used to analyze the data. Fifty-four records conformed to the inclusion criteria (mean age of 21.02 years). Widths of SS and PS increased significantly after surgery (P < 0.001) on the operative sides, while joint spaces of healthy sides and AS of operative sides had no significant changes. Dominant location of condyles of operative sides changed from a posterior position to an anterior position, while healthy sides were mostly centric condylar position no matter preoperatively or postoperatively. Therefore, the results of this study indicate that unilateral arthroscopic disc repositioning significantly increases the posterior and superior spaces of the affected joints, without affecting spaces of the healthy sides. PMID:28361905

Theory of nucleosome corkscrew sliding in the presence of synthetic DNA ligands.

PubMed

Mohammad-Rafiee, Farshid; Kulić, Igor M; Schiessel, Helmut

2004-11-12

Histone octamers show a heat-induced mobility along DNA. Recent theoretical studies have established two mechanisms that are qualitatively and quantitatively compatible with in vitro experiments on nucleosome sliding: octamer repositioning through one-base-pair twist defects and through ten-base-pair bulge defects. A recent experiment demonstrated that the repositioning is strongly suppressed in the presence of minor-groove binding DNA ligands. In the present study, we give a quantitative theory for nucleosome repositioning in the presence of such ligands. We show that the experimentally observed octamer mobilities are consistent with the picture of bound ligands blocking the passage of twist defects through the nucleosome. This strongly supports the model of twist defects inducing a corkscrew motion of the nucleosome as the underlying mechanism of nucleosome sliding. We provide a theoretical estimate of the nucleosomal mobility without adjustable parameters, as a function of ligand concentration, binding affinity, binding site orientation, temperature and DNA anisotropy. Having this mobility in hand, we speculate on the interaction between a nucleosome and a transcribing RNA polymerase, and suggest a novel mechanism that might account for polymerase-induced nucleosome repositioning on short DNA templates.

Repositioning the patient: patient organizations, consumerism, and autonomy in Britain during the 1960s and 1970s.

PubMed

Mold, Alex

2013-01-01

This article explores how and why the patient came to be repositioned as a political actor within British health care during the 1960s and 1970s. Focusing on the role played by patient organizations, it is suggested that the repositioning of the patient needs to be seen in the light of growing demands for greater patient autonomy and the application of consumerist principles to health. Examining the activities of two patient groups-the National Association for the Welfare of Children in Hospital (NAWCH) and the Patients Association (PA)-indicates that while such groups undoubtedly placed more emphasis on individual autonomy, collective concerns did not entirely fall away. The voices of patients, as well as the patient, continued to matter within British health care.

Superior Hypogastric Nerve Block to Reduce Pain After Uterine Artery Embolization: Advanced Technique and Comparison to Epidural Anesthesia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binkert, Christoph A., E-mail: christoph.binkert@ksw.ch; Hirzel, Florian C.; Gutzeit, Andreas

PurposeTo evaluate a modified superior hypogastric nerve block (SHNB) to reduce pain after uterine artery embolization (UAE) compared to epidural anesthesia.Materials and methodsIn this retrospective study, the amount of opiate drugs needed after UAE was compared between SHNB and epidural anesthesia. Eighty one consecutive women (mean age: 43.67 years) were in the SHNB group and 27 consecutive women (mean age: 43.48 years) treated earlier at the same institution in the epidural anesthesia group. UAE was performed from a unilateral femoral artery approach using a 4F catheter. 500–700 or 700–900 μm trisacryl gelatine microspheres were used as embolic agents. The SHNB was performed bymore » advancing a 21G from the abdominal wall below the umbilicus to the anterior portion of the 5th vertebral body. For optimal guidance a cranio-caudal tilt of 5°–15° was used. On a lateral view the correct contrast distribution in front of the vertebral body is confirmed. Then 20 ml local anesthesia (ropivacain 0.75 %) is injected. In case of an asymmetric right–left distribution the needle was repositioned.ResultsAll SHNB were successful without severe complications. The mean time for the SHNB was 4 min 38 s (2 min 38 s–9 min 27 s). The needle was repositioned in average 0.87 times. The opiate dose for the SHNB group was 19.33 ± 22.17 mg which was significantly lower. The average time to receive an opiate drug after SHNB was 4 h 41 min.ConclusionThe SHNB is a safe and minimally time-consuming way to reduce pain after UAE especially within the first 4 h.« less

Biotin-targeted Pluronic(®) P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells.

PubMed

Russo, Annapina; Pellosi, Diogo Silva; Pagliara, Valentina; Milone, Maria Rita; Pucci, Biagio; Caetano, Wilker; Hioka, Noboru; Budillon, Alfredo; Ungaro, Francesca; Russo, Giulia; Quaglia, Fabiana

2016-09-10

With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic(®) P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic(®) F127 was conjugated with biotin, while Pluronic(®) P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P<0.01). To go in depth into the actual therapeutic potential of NCL-loaded PMM, a cisplatin-resistant A549 lung cancer cell line (CPr-A549) was developed and its multidrug resistance tested against common chemotherapeutics. Free NCL was able to overcome chemoresistance showing cytotoxic effects in this cell line ascribable to nucleolar stress, which was associated to a significant increase of the ribosomal protein rpL3 and consequent up-regulation of p21. It is noteworthy that biotin-decorated PMM carrying NCL at low doses demonstrated a significantly higher cytotoxicity than free NCL in CPr-A549. These results point at NCL-based regimen with targeted PMM as a possible second-line chemotherapy for lung cancer showing cisplatin or multidrug resistance. Copyright © 2016 Elsevier B.V. All rights reserved.

Similarity-based prediction for Anatomical Therapeutic Chemical classification of drugs by integrating multiple data sources.

PubMed

Liu, Zhongyang; Guo, Feifei; Gu, Jiangyong; Wang, Yong; Li, Yang; Wang, Dan; Lu, Liang; Li, Dong; He, Fuchu

2015-06-01

Anatomical Therapeutic Chemical (ATC) classification system, widely applied in almost all drug utilization studies, is currently the most widely recognized classification system for drugs. Currently, new drug entries are added into the system only on users' requests, which leads to seriously incomplete drug coverage of the system, and bioinformatics prediction is helpful during this process. Here we propose a novel prediction model of drug-ATC code associations, using logistic regression to integrate multiple heterogeneous data sources including chemical structures, target proteins, gene expression, side-effects and chemical-chemical associations. The model obtains good performance for the prediction not only on ATC codes of unclassified drugs but also on new ATC codes of classified drugs assessed by cross-validation and independent test sets, and its efficacy exceeds previous methods. Further to facilitate the use, the model is developed into a user-friendly web service SPACE ( S: imilarity-based P: redictor of A: TC C: od E: ), which for each submitted compound, will give candidate ATC codes (ranked according to the decreasing probability_score predicted by the model) together with corresponding supporting evidence. This work not only contributes to knowing drugs' therapeutic, pharmacological and chemical properties, but also provides clues for drug repositioning and side-effect discovery. In addition, the construction of the prediction model also provides a general framework for similarity-based data integration which is suitable for other drug-related studies such as target, side-effect prediction etc. The web service SPACE is available at http://www.bprc.ac.cn/space. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton.

PubMed

Kumar, Naveen; Hati, Santanu; Munshi, Parthapratim; Sen, Subhabrata; Sehrawat, Seema; Singh, Shailja

2017-05-01

Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.

Morphometric analysis - Cone beam computed tomography to predict bone quality and quantity.

PubMed

Hohlweg-Majert, B; Metzger, M C; Kummer, T; Schulze, D

2011-07-01

Modified quantitative computed tomography is a method used to predict bone quality and quantify the bone mass of the jaw. The aim of this study was to determine whether bone quantity or quality was detected by cone beam computed tomography (CBCT) combined with image analysis. MATERIALS AND PROCEDURES: Different measurements recorded on two phantoms (Siemens phantom, Comac phantom) were evaluated on images taken with the Somatom VolumeZoom (Siemens Medical Solutions, Erlangen, Germany) and the NewTom 9000 (NIM s.r.l., Verona, Italy) in order to calculate a calibration curve. The spatial relationships of six sample cylinders and the repositioning from four pig skull halves relative to adjacent defined anatomical structures were assessed by means of three-dimensional visualization software. The calibration curves for computer tomography (CT) and cone beam computer tomography (CBCT) using the Siemens phantom showed linear correlation in both modalities between the Hounsfield Units (HU) and bone morphology. A correction factor for CBCT was calculated. Exact information about the micromorphology of the bone cylinders was only available using of micro computer tomography. Cone-beam computer tomography is a suitable choice for analysing bone mass, but, it does not give any information about bone quality. 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

"What Sort of Person Ought I to Be?"--Repositioning EPs in Light of the Children and Families Bill (2013)

ERIC Educational Resources Information Center

Fox, Mark

2015-01-01

The changes brought by the Special Educational Needs and Disability (SEND) code of practice: 0 to 25 years, 2014, is an opportunity for educational psychologists (EPs) to reposition ourselves so that we can improve our contribution to the services for children and young people with special educational needs (SENs) or a disability. Underpinning…

A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

PubMed Central

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten

2013-01-01

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489

A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.

PubMed

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

2013-10-21

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

BRCA-Monet: a breast cancer specific drug treatment mode-of-action network for treatment effective prediction using large scale microarray database

PubMed Central

2013-01-01

Background Connectivity map (cMap) is a recent developed dataset and algorithm for uncovering and understanding the treatment effect of small molecules on different cancer cell lines. It is widely used but there are still remaining challenges for accurate predictions. Method Here, we propose BRCA-MoNet, a network of drug mode of action (MoA) specific to breast cancer, which is constructed based on the cMap dataset. A drug signature selection algorithm fitting the characteristic of cMap data, a quality control scheme as well as a novel query algorithm based on BRCA-MoNet are developed for more effective prediction of drug effects. Result BRCA-MoNet was applied to three independent data sets obtained from the GEO database: Estrodial treated MCF7 cell line, BMS-754807 treated MCF7 cell line, and a breast cancer patient microarray dataset. In the first case, BRCA-MoNet could identify drug MoAs likely to share same and reverse treatment effect. In the second case, the result demonstrated the potential of BRCA-MoNet to reposition drugs and predict treatment effects for drugs not in cMap data. In the third case, a possible procedure of personalized drug selection is showcased. Conclusions The results clearly demonstrated that the proposed BRCA-MoNet approach can provide increased prediction power to cMap and thus will be useful for identification of new therapeutic candidates. Website: The web based application is developed and can be access through the following link http://compgenomics.utsa.edu/BRCAMoNet/ PMID:24564956

Automatic patient alignment system using 3D ultrasound.

PubMed

Kaar, Marcus; Figl, Michael; Hoffmann, Rainer; Birkfellner, Wolfgang; Stock, Markus; Georg, Dietmar; Goldner, Gregor; Hummel, Johann

2013-04-01

Recent developments in radiation therapy such as intensity modulated radiotherapy (IMRT) or dose painting promise to provide better dose distribution on the tumor. For effective application of these methods the exact positioning of the patient and the localization of the irradiated organ and surrounding structures is crucial. Especially with respect to the treatment of the prostate, ultrasound (US) allows for differentiation between soft tissue and was therefore applied by various repositioning systems, such as BAT or Clarity. The authors built a new system which uses 3D US at both sites, the CT room and the intervention room and applied a 3D/3D US/US registration for automatic repositioning. In a first step the authors applied image preprocessing methods to prepare the US images for an optimal registration process. For the 3D/3D registration procedure five different metrics were evaluated. To find the image metric which fits best for a particular patient three 3D US images were taken at the CT site and registered to each other. From these results an US registration error was calculated. The most successful image metric was then applied for the US/US registration process. The success of the whole repositioning method was assessed by taking the results of an ExacTrac system as golden standard. The US/US registration error was found to be 2.99 ± 1.54 mm with respect to the mutual information metric by Mattes (eleven patients) which revealed to be the most suitable of the assessed metrics. For complete repositioning chain the error amounted to 4.15 ± 1.20 mm (ten patients). The authors developed a system for patient repositioning which works automatically without the necessity of user interaction with an accuracy which seems to be suitable for clinical application.

Bladder perforation during sling procedures: diagnosis and management of injury.

PubMed

Israfil-Bayli, F; Bulchandani, S; Parsons, M; Jackson, S; Toozs-Hobson, P

2014-05-01

Midurethral slings are an effective and minimally invasive treatment for stress urinary incontinence. One of the most common intraoperative complications is bladder perforation, complicating between 2 and 10% of all operations, and on average 4.7%. It is usually corrected during surgery, with repositioning of the trocars. The purpose of this video is to demonstrate a method of replacing the trocars under direct vision. This video exhibits a bladder perforation during insertion of a retropubic midurethral sling (Advantage Fit; Boston Scientific) and gives a step-by step guide to the removal and repositioning of the sling under direct visualisation. Repositioning of the trocars under direct vision in cases of bladder perforation may have numerous advantages. It may prevent damage to the urethra, possibly reduce the risk of postoperative infection and may be beneficial for trainees.

Vaginal Pessary for Uterine Repositioning During High-Intensity Focused Ultrasound Ablation of Uterine Leiomyomas

PubMed Central

Pulanic, Tajana Klepac; Venkatesan, Aradhana M.; Segars, James; Sokka, Sham; Wood, Bradford J.; Stratton, Pamela

2015-01-01

In order to ensure safe magnetic resonance-guided high-intensity focused ultrasound ablation of uterine leiomyomas, ultrasound beam path should be free of intervening scar and bowel. Pre-treatment magnetic resonance imaging of a 9cm long and 7.7cm wide leiomyomatous uterus in a 39-year-old woman with menorrhagia and abdominopelvic pain initially demonstrated a focused ultrasound treatment path without bowel between the uterus and abdominal wall. On the day of ablation, however, multiple loops of bowel were observed in the ultrasound beam path by magnetic resonance imaging. Uterine repositioning was accomplished with a 76 mm donut vaginal pessary which anteverted the fundus and successfully displaced bowel. A vaginal pessary may aid in repositioning an axial or retroverted uterus to enable ablation of uterine leiomyomas. PMID:26584482

Vaginal Pessary for Uterine Repositioning during High-Intensity Focused Ultrasound Ablation of Uterine Leiomyomas.

PubMed

Klepac Pulanic, Tajana; Venkatesan, Aradhana M; Segars, James; Sokka, Sham; Wood, Bradford J; Stratton, Pamela

2016-01-01

In order to ensure safe magnetic resonance-guided, high-intensity focused, ultrasound ablation of uterine leiomyomas, the ultrasound beam path should be free of intervening scar and bowel. Pre-treatment MRI of a 9-cm long and 7.7-cm wide leiomyomatous uterus in a 39-year-old woman with menorrhagia and abdominopelvic pain initially demonstrated a focused ultrasound treatment path without a bowel between the uterus and the abdominal wall. On the day of ablation, however, multiple loops of bowel were observed in the ultrasound beam path by MRI. Uterine repositioning was accomplished with a 76-mm donut vaginal pessary, which anteverted the fundus and successfully displaced the bowel. A vaginal pessary may aid in repositioning an axial or retroverted uterus to enable ablation of uterine leiomyomas. © 2015 S. Karger AG, Basel.

Benchmarks for target tracking

NASA Astrophysics Data System (ADS)

Dunham, Darin T.; West, Philip D.

2011-09-01

The term benchmark originates from the chiseled horizontal marks that surveyors made, into which an angle-iron could be placed to bracket ("bench") a leveling rod, thus ensuring that the leveling rod can be repositioned in exactly the same place in the future. A benchmark in computer terms is the result of running a computer program, or a set of programs, in order to assess the relative performance of an object by running a number of standard tests and trials against it. This paper will discuss the history of simulation benchmarks that are being used by multiple branches of the military and agencies of the US government. These benchmarks range from missile defense applications to chemical biological situations. Typically, a benchmark is used with Monte Carlo runs in order to tease out how algorithms deal with variability and the range of possible inputs. We will also describe problems that can be solved by a benchmark.

FDA approved drugs complexed to their targets: evaluating pose prediction accuracy of docking protocols.

PubMed

Bohari, Mohammed H; Sastry, G Narahari

2012-09-01

Efficient drug discovery programs can be designed by utilizing existing pools of knowledge from the already approved drugs. This can be achieved in one way by repositioning of drugs approved for some indications to newer indications. Complex of drug to its target gives fundamental insight into molecular recognition and a clear understanding of putative binding site. Five popular docking protocols, Glide, Gold, FlexX, Cdocker and LigandFit have been evaluated on a dataset of 199 FDA approved drug-target complexes for their accuracy in predicting the experimental pose. Performance for all the protocols is assessed at default settings, with root mean square deviation (RMSD) between the experimental ligand pose and the docked pose of less than 2.0 Å as the success criteria in predicting the pose. Glide (38.7 %) is found to be the most accurate in top ranked pose and Cdocker (58.8 %) in top RMSD pose. Ligand flexibility is a major bottleneck in failure of docking protocols to correctly predict the pose. Resolution of the crystal structure shows an inverse relationship with the performance of docking protocol. All the protocols perform optimally when a balanced type of hydrophilic and hydrophobic interaction or dominant hydrophilic interaction exists. Overall in 16 different target classes, hydrophobic interactions dominate in the binding site and maximum success is achieved for all the docking protocols in nuclear hormone receptor class while performance for the rest of the classes varied based on individual protocol.

Auranofin Induces Lethal Oxidative and Endoplasmic Reticulum Stress and Exerts Potent Preclinical Activity against Chronic Lymphocytic Leukemia

PubMed Central

Fiskus, Warren; Saba, Nakhle; Shen, Min; Ghias, Mondana; Liu, Jinyun; Gupta, Soumyasri Das; Chauhan, Lata; Rao, Rekha; Gunewardena, Sumedha; Schorno, Kevin; Austin, Christopher P.; Maddocks, Kami; Byrd, John; Melnick, Ari; Huang, Peng; Wiestner, Adrian; Bhalla, Kapil N.

2014-01-01

Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL. PMID:24599128

Targeting Phosphatidylinositol 4-Kinase IIIα for Radiosensitization: A Potential Model of Drug Repositioning Using an Anti-Hepatitis C Viral Agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwon, Jeanny; Kim, Dan Hyo; Park, Ji Min

Purpose: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti–hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells. Methods and Materials: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed. Results: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitorymore » concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy. Conclusion: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.« less

Effect of Repositioning Maneuver Type and Postmaneuver Restrictions on Vertigo and Dizziness in Benign Positional Paroxysmal Vertigo

PubMed Central

Toupet, Michel; Ferrary, Evelyne; Bozorg Grayeli, Alexis

2012-01-01

Introduction. To compare the efficiency of Epley (Ep) and Sémont-Toupet (ST) repositioning maneuvers and to evaluate postmaneuver restriction effect on short-term vertigo and dizziness after repositioning maneuvers by an analog visual scale (VAS) in benign positional paroxysmal vertigo (BPPV). Material and Methods. 226 consecutive adult patients with posterior canal BPPV were included. Patients were randomized into 2 different maneuver sequence groups (n = 113): 2 ST then 1 Ep or 2 Ep then 1 ST. Each group of sequence was randomized into 2 subgroups: with or without postmaneuver restrictions. Vertigo and dizziness were assessed from days 0 to 5 by VAS. Results. There was no difference between vertigo scores between Ep and ST groups. Dizziness scores were higher in Ep group during the first 3 days but became similar to those of ST group at days 4 and 5. ST maneuvers induced liberatory signs more frequently than Ep (58% versus 42% resp., P < 0.01, Fisher's test). After repositioning maneuvers, VAS scores decreased similarly in patients with and without liberatory signs. Postmaneuver restrictions did not influence VAS scores. Conclusion. Even if ST showed a higher rate of liberatory signs than Ep in this series, VAS scores were not influenced by these signs. PMID:22973168

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

PubMed Central

Akala, Hoseah M.; Macharia, Rosaline W.; Juma, Dennis W.; Cheruiyot, Agnes C.; Andagalu, Ben; Brown, Mathew L.; El-Shemy, Hany A.; Nyanjom, Steven G.

2017-01-01

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens. PMID:29088219

Prediction of anti-cancer drug response by kernelized multi-task learning.

PubMed

Tan, Mehmet

2016-10-01

Chemotherapy or targeted therapy are two of the main treatment options for many types of cancer. Due to the heterogeneous nature of cancer, the success of the therapeutic agents differs among patients. In this sense, determination of chemotherapeutic response of the malign cells is essential for establishing a personalized treatment protocol and designing new drugs. With the recent technological advances in producing large amounts of pharmacogenomic data, in silico methods have become important tools to achieve this aim. Data produced by using cancer cell lines provide a test bed for machine learning algorithms that try to predict the response of cancer cells to different agents. The potential use of these algorithms in drug discovery/repositioning and personalized treatments motivated us in this study to work on predicting drug response by exploiting the recent pharmacogenomic databases. We aim to improve the prediction of drug response of cancer cell lines. We propose to use a method that employs multi-task learning to improve learning by transfer, and kernels to extract non-linear relationships to predict drug response. The method outperforms three state-of-the-art algorithms on three anti-cancer drug screen datasets. We achieved a mean squared error of 3.305 and 0.501 on two different large scale screen data sets. On a recent challenge dataset, we obtained an error of 0.556. We report the methodological comparison results as well as the performance of the proposed algorithm on each single drug. The results show that the proposed method is a strong candidate to predict drug response of cancer cell lines in silico for pre-clinical studies. The source code of the algorithm and data used can be obtained from http://mtan.etu.edu.tr/Supplementary/kMTrace/. Copyright © 2016 Elsevier B.V. All rights reserved.

Exploring drug-target interaction networks of illicit drugs.

PubMed

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning.

Exploring drug-target interaction networks of illicit drugs

PubMed Central

2013-01-01

Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. Results In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. Conclusions This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning. PMID:24268016

Evaluation of ceiling lifts: transfer time, patient comfort and staff perceptions.

PubMed

Alamgir, Hasanat; Li, Olivia Wei; Yu, Shicheng; Gorman, Erin; Fast, Catherine; Kidd, Catherine

2009-09-01

Mechanical lifting devices have been developed to reduce healthcare worker injuries related to patient handling. The purpose of this study was to evaluate ceiling lifts in comparison to floor lifts based on transfer time, patient comfort and staff perceptions in three long-term care facilities with varying ceiling lift coverage. The time required to transfer or reposition patients along with patient comfort levels were recorded for 119 transfers. Transfers performed with ceiling lifts required on average less time (bed to chair transfers: 156.9 seconds for ceiling lift, 273.6 seconds for floor lift) and were found to be more comfortable for patients. In the three facilities, 143 healthcare workers were surveyed on their perceptions of patient handling tasks and equipment. For both transferring and repositioning tasks, staff preferred to use ceiling lifts and also found them to be less physically demanding. Further investigation is needed on repositioning tasks to ensure safe practice.

Condylar repositioning using centric relation bite in bimaxillary surgery

PubMed Central

Lee, Chang-Youn; Jang, Chang-Su; Kim, Ju-Won; Kim, Jwa-Young

2013-01-01

Objective The purpose of this study was to evaluate displacement of the mandibular condyle after orthognathic surgery using a condylar-repositioning device. Methods The patient group comprised 20 adults who underwent bimaxillary surgery between August 2008 and July 2011. The degree of condylar displacement was measured by pre- and postoperative tomographic analysis using centric relation bite and a wire during surgery. A survey assessing temporomandibular joint (TMJ) sound, pain, and locking was performed. The 20 tomographs and surveys were analyzed using the Wilcoxon signed-rank test and McNemar's test, respectively. Results No significant changes were observed in the anterior, superior, or posterior joint space of the TMJ (p > 0.05). In addition, no significant change was observed in TMJ sound (p > 0.05). However, TMJ pain and locking both decreased significantly after surgery (p < 0.05). Conclusions Due to its simplicity, this method may be feasible and useful for repositioning condyles. PMID:23671832

Optic neuropathy after anterior communicating artery aneurysm clipping: 3 cases and techniques to address a correctable pitfall.

PubMed

Linzey, Joseph R; Chen, Kevin S; Savastano, Luis; Thompson, B Gregory; Pandey, Aditya S

2018-06-01

Brain shifts following microsurgical clip ligation of anterior communicating artery (ACoA) aneurysms can lead to mechanical compression of the optic nerve by the clip. Recognition of this condition and early repositioning of clips can lead to reversal of vision loss. The authors identified 3 patients with an afferent pupillary defect following microsurgical clipping of ACoA aneurysms. Different treatment options were used for each patient. All patients underwent reexploration, and the aneurysm clips were repositioned to prevent clip-related compression of the optic nerve. Near-complete restoration of vision was achieved at the last clinic follow-up visit in all 3 patients. Clip ligation of ACoA aneurysms has the potential to cause clip-related compression of the optic nerve. Postoperative visual examination is of utmost importance, and if any changes are discovered, reexploration should be considered as repositioning of the clips may lead to resolution of visual deterioration.

Starshade Observation Scheduling for WFIRST

NASA Astrophysics Data System (ADS)

Soto, Gabriel; Garrett, Daniel; Delacroix, Christian; Savransky, Dmitry

2018-01-01

An exoplanet direct imaging mission can employ an external starshade for starlight suppression to achieve higher contrasts and potentially higher throughput than with an internal coronagraph. This separately-launched starshade spacecraft is assumed to maintain a single, constant separation distance from the space telescope—for this study, the Wide Field Infrared Survey Telescope (WFIRST)—based on a designated inner working angle during integration times. The science yield of such a mission can be quantified using the Exoplanet Open-Source Imaging Simulator (EXOSIMS): this simulator determines the distributions of mission outcomes, such as the types and amount of exoplanet detections, based on ensembles of end-to-end simulations of the mission. This study adds a starshade class to the survey simulation module of EXOSIMS and outlines a method for efficiently determining observation schedules. The new starshade class solves boundary value problems using circular restricted three-body dynamics to find fast, high-accuracy estimates of the starshade motion while repositioning between WFIRST observations. Fuel usage dictates the mission lifetime of the starshade given its limited fuel supply and is dominated by the Δv used to reposition the starshade between the LOS of different targets; the repositioning time-of-flight is kept constant in this study. A starshade burns less fuel to reach certain target stars based on their relative projected positions on a skymap; other targets with costly transfers can be filtered out to increase the starshade mission duration. Because the initial target list can consist of nearly 2000 stars, calculating the Δv required to move the starshade to every other star on the target list would be too computationally expensive and renders running ensembles of survey simulations infeasible. Assuming the starshade begins its transfer at the LOS of a certain star, a Δv curve is approximated for the remaining target stars based on their right ascension or declination angle, depending on the starting and ending position of WFIRST on its halo orbit. The required Δv for a given star can be quickly interpolated and used to filter out stars in the target list.

Accuracy of a Computer-Aided Surgical Simulation (CASS) Protocol for Orthognathic Surgery: A Prospective Multicenter Study

PubMed Central

Hsu, Sam Sheng-Pin; Gateno, Jaime; Bell, R. Bryan; Hirsch, David L.; Markiewicz, Michael R.; Teichgraeber, John F.; Zhou, Xiaobo; Xia, James J.

2012-01-01

Purpose The purpose of this prospective multicenter study was to assess the accuracy of a computer-aided surgical simulation (CASS) protocol for orthognathic surgery. Materials and Methods The accuracy of the CASS protocol was assessed by comparing planned and postoperative outcomes of 65 consecutive patients enrolled from 3 centers. Computer-generated surgical splints were used for all patients. For the genioplasty, one center utilized computer-generated chin templates to reposition the chin segment only for patients with asymmetry. Standard intraoperative measurements were utilized without the chin templates for the remaining patients. The primary outcome measurements were linear and angular differences for the maxilla, mandible and chin when the planned and postoperative models were registered at the cranium. The secondary outcome measurements were: maxillary dental midline difference between the planned and postoperative positions; and linear and angular differences of the chin segment between the groups with and without the use of the template. The latter was measured when the planned and postoperative models were registered at mandibular body. Statistical analyses were performed, and the accuracy was reported using root mean square deviation (RMSD) and Bland and Altman's method for assessing measurement agreement. Results In the primary outcome measurements, there was no statistically significant difference among the 3 centers for the maxilla and mandible. The largest RMSD was 1.0mm and 1.5° for the maxilla, and 1.1mm and 1.8° for the mandible. For the chin, there was a statistically significant difference between the groups with and without the use of the chin template. The chin template group showed excellent accuracy with largest positional RMSD of 1.0mm and the largest orientational RSMD of 2.2°. However, larger variances were observed in the group not using the chin template. This was significant in anteroposterior and superoinferior directions, as in pitch and yaw orientations. In the secondary outcome measurements, the RMSD of maxillary dental midline positions was 0.9mm. When registered at the body of the mandible, the linear and angular differences of the chin segment between the groups with and without the use of the chin template were consistent with the results found in the primary outcome measurements. Conclusion Using the CASS protocol, the computerized plan can be accurately and consistently transferred to the patient to position the maxilla and mandible at the time of surgery. The computer-generated chin template provides more accuracy in repositioning the chin segment than the intraoperative measurements. PMID:22695016

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

PubMed

Islam, Tania; Rahman, Rezanur; Gov, Esra; Turanli, Beste; Gulfidan, Gizem; Haque, Anwarul; Arga, Kazım Yalçın; Haque Mollah, Nurul

2018-06-01

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Reconstruction of a Severely Atrophied Alveolar Ridge by Computer-Aided Gingival Simulation and 3D-Printed Surgical Guide: A Case Report.

PubMed

Song, In-Seok; Lee, Mi-Ran; Ryu, Jae-Jun; Lee, Ui-Lyong

Dental implants positioned in severely atrophied anterior maxillae require esthetic or functional compromises. This case report describes the rehabilitation of a severely atrophied alveolar ridge with a three-dimensional (3D) computer-aided design/computer-aided manufacture (CAD/CAM) surgical guide. A 50-year-old woman had a severely atrophied anterior maxilla with unfavorably positioned dental implants. Functional and esthetic prosthodontic restoration was difficult to achieve. An anterior segmental osteotomy was planned to reposition the dental implants. A 3D surgical guide was designed for precise relocation of the segment. The surgical guide firmly grasped the impression copings of the dental implants, minimizing surgical errors. Three-dimensional gingival simulation was used preoperatively to estimate the appropriate position of the gingiva. Rigid fixation to the surrounding bone allowed immobilization of the implant-bone segment. Satisfactory esthetic and functional outcomes were attained 6 months after surgery. Finally, a severely atrophied alveolar ridge with unfavorably positioned dental implants was recovered with minimal esthetic and functional deterioration using gingival simulation and a 3D CAD/CAM surgical guide.

One-carbon metabolism: an aging-cancer crossroad for the gerosuppressant metformin.

PubMed

Menendez, Javier A; Joven, Jorge

2012-12-01

The gerosuppressant metformin operates as an efficient inhibitor of the mTOR/S6K1 gerogenic pathway due to its ability to ultimately activate the energy-sensor AMPK. If an aging-related decline in the AMPK sensitivity to cellular stress is a crucial event for mTOR-driven aging and aging-related diseases, including cancer, unraveling new proximal causes through which AMPK activation endows its gerosuppressive effects may offer not only a better understanding of metformin function but also the likely possibility of repositioning our existing gerosuppressant drugs. Here we provide our perspective on recent findings suggesting that de novo biosynthesis of purine nucleotides, which is based on the metabolism of one-carbon compounds, is a new target for metformin's actions at the crossroads of aging and cancer.

Predicting drug-target interactions using restricted Boltzmann machines.

PubMed

Wang, Yuhao; Zeng, Jianyang

2013-07-01

In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Software and datasets are available on request. Supplementary data are available at Bioinformatics online.

Variations in the axis of motion during head repositioning--a comparison of subjects with whiplash-associated disorders or non-specific neck pain and healthy controls.

PubMed

Grip, Helena; Sundelin, Gunnevi; Gerdle, Björn; Karlsson, J Stefan

2007-10-01

The ability to reproduce head position can be affected in patients after a neck injury. The repositioning error is commonly used as a measure of proprioception, but variations in the movement might provide additional information. The axis of motion and target performance were analyzed during a head repositioning task (flexion, extension and side rotations) for 24 control subjects, 22 subjects with whiplash-associated disorders and 21 with non-specific neck pain. Questionnaires regarding pain intensity and fear avoidance were collected. Head position and axis of motion parameters were calculated using a helical axis model with a moving window of 4 degrees . During flexion the whiplash group had a larger constant repositioning error than the control group (-1.8(2.9) degrees vs. 0.1(2.4) degrees , P=0.04). The axis was more inferior in both neck pain groups (12.0(1.6)cm vs. 14.5(2.0)cm, P<0.05) indicating movement at a lower level in the spine. Including pain intensity from shoulder and neck region as covariates showed an effect on the axis position (P=0.03 and 0.04). During axial rotation to the left there was more variation in axis direction for neckpain groups as compared with controls (4.0(1.7) degrees and 3.7(2.4) degrees vs. 2.3(1.9) degrees , P=0.01 and 0.05). No significant difference in fear avoidance was found between the two neck pain groups. Measuring variation in the axis of motion together with target performance gives objective measures on proprioceptive ability that are difficult to quantify by visual inspection. Repositioning errors were in general small, suggesting it is not sufficient as a single measurement variable in a clinical situation, but should be measured in combination with other tests, such as range of motion.

Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005 - 2013).

PubMed

Carta, Fabrizio; Supuran, Claudiu T

2013-01-01

The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension. The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented. This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.

Dosimetric and radiobiological consequences of computed tomography-guided adaptive strategies for intensity modulated radiation therapy of the prostate.

PubMed

Battista, Jerry J; Johnson, Carol; Turnbull, David; Kempe, Jeff; Bzdusek, Karl; Van Dyk, Jacob; Bauman, Glenn

2013-12-01

To examine a range of scenarios for image-guided adaptive radiation therapy of prostate cancer, including different schedules for megavoltage CT imaging, patient repositioning, and dose replanning. We simulated multifraction dose distributions with deformable registration using 35 sets of megavoltage CT scans of 13 patients. We computed cumulative dose-volume histograms, from which tumor control probabilities and normal tissue complication probabilities (NTCPs) for rectum were calculated. Five-field intensity modulated radiation therapy (IMRT) with 18-MV x-rays was planned to achieve an isocentric dose of 76 Gy to the clinical target volume (CTV). The differences between D95, tumor control probability, V70Gy, and NTCP for rectum, for accumulated versus planned dose distributions, were compared for different target volume sizes, margins, and adaptive strategies. The CTV D95 for IMRT treatment plans, averaged over 13 patients, was 75.2 Gy. Using the largest CTV margins (10/7 mm), the D95 values accumulated over 35 fractions were within 2% of the planned value, regardless of the adaptive strategy used. For tighter margins (5 mm), the average D95 values dropped to approximately 73.0 Gy even with frequent repositioning, and daily replanning was necessary to correct this deficit. When personalized margins were applied to an adaptive CTV derived from the first 6 treatment fractions using the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm, target coverage could be maintained using a single replan 1 week into therapy. For all approaches, normal tissue parameters (rectum V(70Gy) and NTCP) remained within acceptable limits. The frequency of adaptive interventions depends on the size of the CTV combined with target margins used during IMRT optimization. The application of adaptive target margins (<5 mm) to an adaptive CTV determined 1 week into therapy minimizes the need for subsequent dose replanning. Copyright © 2013 Elsevier Inc. All rights reserved.

Haptics in forensics: the possibilities and advantages in using the haptic device for reconstruction approaches in forensic science.

PubMed

Buck, Ursula; Naether, Silvio; Braun, Marcel; Thali, Michael

2008-09-18

Non-invasive documentation methods such as surface scanning and radiological imaging are gaining in importance in the forensic field. These three-dimensional technologies provide digital 3D data, which are processed and handled in the computer. However, the sense of touch gets lost using the virtual approach. The haptic device enables the use of the sense of touch to handle and feel digital 3D data. The multifunctional application of a haptic device for forensic approaches is evaluated and illustrated in three different cases: the representation of bone fractures of the lower extremities, by traffic accidents, in a non-invasive manner; the comparison of bone injuries with the presumed injury-inflicting instrument; and in a gunshot case, the identification of the gun by the muzzle imprint, and the reconstruction of the holding position of the gun. The 3D models of the bones are generated from the Computed Tomography (CT) images. The 3D models of the exterior injuries, the injury-inflicting tools and the bone injuries, where a higher resolution is necessary, are created by the optical surface scan. The haptic device is used in combination with the software FreeForm Modelling Plus for touching the surface of the 3D models to feel the minute injuries and the surface of tools, to reposition displaced bone parts and to compare an injury-causing instrument with an injury. The repositioning of 3D models in a reconstruction is easier, faster and more precisely executed by means of using the sense of touch and with the user-friendly movement in the 3D space. For representation purposes, the fracture lines of bones are coloured. This work demonstrates that the haptic device is a suitable and efficient application in forensic science. The haptic device offers a new way in the handling of digital data in the virtual 3D space.

Successful Excision of Gynecomastia with Nipple Repositioning Technique Utilizing the Dermoglandular Flap

PubMed Central

Motamed, Sadrollah; Hassanpour, Seyed Esmail; Moosavizadeh, Seyed Mehdi; Heidari, Ataollah; Rouientan, Abdoreza; Nazemian, Mahmood

2015-01-01

There are many surgical techniques for treating gynecomastia. We report a new surgical technique in an adolescent with fatty glandular gynecomastia grade III, who was referred from an endocrinologist to our clinic. We excised the gynecomastia with nipple repositioning utilizing the dermoglandular flap (about 1 cm thickness and 10 cm width). After one month, no complication was detected and the patient was satisfied with his new breasts. We suggest this technique for fatty glandular gynecomastia grade III. PMID:26284186

Scuba Weights

NASA Technical Reports Server (NTRS)

1995-01-01

The Attitude Adjuster is a system for weight repositioning corresponding to a SCUBA diver's changing positions. Compact tubes on the diver's air tank permit controlled movement of lead balls within the Adjuster, automatically repositioning when the diver changes position. Manufactured by Think Tank Technologies, the system is light and small, reducing drag and energy requirements and contributing to lower air consumption. The Mid-Continent Technology Transfer Center helped the company with both technical and business information and arranged for the testing at Marshall Space Flight Center's Weightlessness Environmental Training Facility for astronauts.

[Orthognathic surgery, master-piece of maxillo-facial surgery].

PubMed

Reychler, H

2001-01-01

Orthognathic surgery is this field of the maxillofacial surgery which aims to reposition the jaws or some segments of these jaws when masticatory dysfunctions are evident. This tridimensional repositioning in the craniofacial skeleton allows to restore the masticatory function by means of osteotomies, which must be followed either by preoperative simulated bony displacements or by callus bone distraction. Not only are the functional benefits evident on the dental, articular and neuromuscular levels, but also a facial esthetic harmony can almost be obtained.

Combustor oscillating pressure stabilization and method

DOEpatents

Gemmen, R.S.; Richards, G.A.; Yip, M.T.J.; Robey, E.H.; Cully, S.R.; Addis, R.E.

1998-08-11

High dynamic pressure oscillations in hydrocarbon-fueled combustors typically occur when the transport time of the fuel to the flame front is at some fraction of the acoustic period. These oscillations are reduced to acceptably lower levels by restructuring or repositioning the flame front in the combustor to increase the transport time. A pilot flame front located upstream of the oscillating flame and pulsed at a selected frequency and duration effectively restructures and repositions the oscillating flame in the combustor to alter the oscillation-causing transport time. 7 figs.

Accuracy of a computer-aided surgical simulation protocol for orthognathic surgery: a prospective multicenter study.

PubMed

Hsu, Sam Sheng-Pin; Gateno, Jaime; Bell, R Bryan; Hirsch, David L; Markiewicz, Michael R; Teichgraeber, John F; Zhou, Xiaobo; Xia, James J

2013-01-01

The purpose of this prospective multicenter study was to assess the accuracy of a computer-aided surgical simulation (CASS) protocol for orthognathic surgery. The accuracy of the CASS protocol was assessed by comparing planned outcomes with postoperative outcomes of 65 consecutive patients enrolled from 3 centers. Computer-generated surgical splints were used for all patients. For the genioplasty, 1 center used computer-generated chin templates to reposition the chin segment only for patients with asymmetry. Standard intraoperative measurements were used without the chin templates for the remaining patients. The primary outcome measurements were the linear and angular differences for the maxilla, mandible, and chin when the planned and postoperative models were registered at the cranium. The secondary outcome measurements were the maxillary dental midline difference between the planned and postoperative positions and the linear and angular differences of the chin segment between the groups with and without the use of the template. The latter were measured when the planned and postoperative models were registered at the mandibular body. Statistical analyses were performed, and the accuracy was reported using root mean square deviation (RMSD) and the Bland-Altman method for assessing measurement agreement. In the primary outcome measurements, there was no statistically significant difference among the 3 centers for the maxilla and mandible. The largest RMSDs were 1.0 mm and 1.5° for the maxilla and 1.1 mm and 1.8° for the mandible. For the chin, there was a statistically significant difference between the groups with and without the use of the chin template. The chin template group showed excellent accuracy, with the largest positional RMSD of 1.0 mm and the largest orientation RMSD of 2.2°. However, larger variances were observed in the group not using the chin template. This was significant in the anteroposterior and superoinferior directions and the in pitch and yaw orientations. In the secondary outcome measurements, the RMSD of the maxillary dental midline positions was 0.9 mm. When registered at the body of the mandible, the linear and angular differences of the chin segment between the groups with and without the use of the chin template were consistent with the results found in the primary outcome measurements. Using this computer-aided surgical simulation protocol, the computerized plan can be transferred accurately and consistently to the patient to position the maxilla and mandible at the time of surgery. The computer-generated chin template provides greater accuracy in repositioning the chin segment than the intraoperative measurements. Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Automatic construction of patient-specific finite-element mesh of the spine from IVDs and vertebra segmentations

NASA Astrophysics Data System (ADS)

Castro-Mateos, Isaac; Pozo, Jose M.; Lazary, Aron; Frangi, Alejandro F.

2016-03-01

Computational medicine aims at developing patient-specific models to help physicians in the diagnosis and treatment selection for patients. The spine, and other skeletal structures, is an articulated object, composed of rigid bones (vertebrae) and non-rigid parts (intervertebral discs (IVD), ligaments and muscles). These components are usually extracted from different image modalities, involving patient repositioning. In the case of the spine, these models require the segmentation of IVDs from MR and vertebrae from CT. In the literature, there exists a vast selection of segmentations methods, but there is a lack of approaches to align the vertebrae and IVDs. This paper presents a method to create patient-specific finite element meshes for biomechanical simulations, integrating rigid and non-rigid parts of articulated objects. First, the different parts are aligned in a complete surface model. Vertebrae extracted from CT are rigidly repositioned in between the IVDs, initially using the IVDs location and then refining the alignment using the MR image with a rigid active shape model algorithm. Finally, a mesh morphing algorithm, based on B-splines, is employed to map a template finite-element (volumetric) mesh to the patient-specific surface mesh. This morphing reduces possible misalignments and guarantees the convexity of the model elements. Results show that the accuracy of the method to align vertebrae into MR, together with IVDs, is similar to that of the human observers. Thus, this method is a step forward towards the automation of patient-specific finite element models for biomechanical simulations.

An integrated structure- and system-based framework to identify new targets of metabolites and known drugs

PubMed Central

Naveed, Hammad; Hameed, Umar S.; Harrus, Deborah; Bourguet, William; Arold, Stefan T.; Gao, Xin

2015-01-01

Motivation: The inherent promiscuity of small molecules towards protein targets impedes our understanding of healthy versus diseased metabolism. This promiscuity also poses a challenge for the pharmaceutical industry as identifying all protein targets is important to assess (side) effects and repositioning opportunities for a drug. Results: Here, we present a novel integrated structure- and system-based approach of drug-target prediction (iDTP) to enable the large-scale discovery of new targets for small molecules, such as pharmaceutical drugs, co-factors and metabolites (collectively called ‘drugs’). For a given drug, our method uses sequence order–independent structure alignment, hierarchical clustering and probabilistic sequence similarity to construct a probabilistic pocket ensemble (PPE) that captures promiscuous structural features of different binding sites on known targets. A drug’s PPE is combined with an approximation of its delivery profile to reduce false positives. In our cross-validation study, we use iDTP to predict the known targets of 11 drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs—two that are of high pharmacological interest, the peroxisome proliferator-activated receptor gamma and the oncogene B-cell lymphoma 2, were successfully validated through in vitro binding experiments. Our method is broadly applicable for the prediction of protein-small molecule interactions with several novel applications to biological research and drug development. Availability and implementation: The program, datasets and results are freely available to academic users at http://sfb.kaust.edu.sa/Pages/Software.aspx. Contact: xin.gao@kaust.edu.sa and stefan.arold@kaust.edu.sa Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26286808

Turtle embryos move to optimal thermal environments within the egg.

PubMed

Zhao, Bo; Li, Teng; Shine, Richard; Du, Wei-Guo

2013-08-23

A recent study demonstrated that the embryos of soft-shelled turtles can reposition themselves within their eggs to exploit locally warm conditions. In this paper, we ask whether turtle embryos actively seek out optimal thermal environments for their development, as do post-hatching individuals. Specifically, (i) do reptile embryos move away from dangerously high temperatures as well as towards warm temperatures? and (ii) is such embryonic movement due to active thermoregulation, or (more simply) to passive embryonic repositioning caused by local heat-induced changes in viscosity of fluids within the egg? Our experiments with an emydid turtle (Chinemys reevesii) show that embryos avoid dangerously high temperatures by moving to cooler regions of the egg. The repositioning of embryos is an active rather than passive process: live embryos move towards a heat source, whereas dead ones do not. Overall, our results suggest that behavioural thermoregulation by turtle embryos is genuinely analogous to the thermoregulatory behaviour exhibited by post-hatching ectotherms.

Chromosome territories reposition during DNA damage-repair response

PubMed Central

2013-01-01

Background Local higher-order chromatin structure, dynamics and composition of the DNA are known to determine double-strand break frequencies and the efficiency of repair. However, how DNA damage response affects the spatial organization of chromosome territories is still unexplored. Results Our report investigates the effect of DNA damage on the spatial organization of chromosome territories within interphase nuclei of human cells. We show that DNA damage induces a large-scale spatial repositioning of chromosome territories that are relatively gene dense. This response is dose dependent, and involves territories moving from the nuclear interior to the periphery and vice versa. Furthermore, we have found that chromosome territory repositioning is contingent upon double-strand break recognition and damage sensing. Importantly, our results suggest that this is a reversible process where, following repair, chromosome territories re-occupy positions similar to those in undamaged control cells. Conclusions Thus, our report for the first time highlights DNA damage-dependent spatial reorganization of whole chromosomes, which might be an integral aspect of cellular damage response. PMID:24330859

Turtle embryos move to optimal thermal environments within the egg

PubMed Central

Zhao, Bo; Li, Teng; Shine, Richard; Du, Wei-Guo

2013-01-01

A recent study demonstrated that the embryos of soft-shelled turtles can reposition themselves within their eggs to exploit locally warm conditions. In this paper, we ask whether turtle embryos actively seek out optimal thermal environments for their development, as do post-hatching individuals. Specifically, (i) do reptile embryos move away from dangerously high temperatures as well as towards warm temperatures? and (ii) is such embryonic movement due to active thermoregulation, or (more simply) to passive embryonic repositioning caused by local heat-induced changes in viscosity of fluids within the egg? Our experiments with an emydid turtle (Chinemys reevesii) show that embryos avoid dangerously high temperatures by moving to cooler regions of the egg. The repositioning of embryos is an active rather than passive process: live embryos move towards a heat source, whereas dead ones do not. Overall, our results suggest that behavioural thermoregulation by turtle embryos is genuinely analogous to the thermoregulatory behaviour exhibited by post-hatching ectotherms. PMID:23760168

Physical activity levels and torso orientations of hospitalized patients at risk of developing a pressure injury: an observational study.

PubMed

Chaboyer, Wendy; Mills, Peter M; Roberts, Shelley; Latimer, Sharon

2015-02-01

Pressure injury guidelines recommend regular repositioning yet patients' mobility and repositioning patterns are unknown. An observational study using activity monitors was undertaken to describe the 24 h activity patterns of 84 hospitalized patients at risk of developing a pressure injury. The vast majority of participants' time was spent in the sedentary activity range (94% ± 3%) followed by the light range (5% ± 4 %). Patients changed their posture a median of 94 (interquartile range 48) time in the 24-h period (range 11-154), or ≈ 3.8 times per hour. Although a main focus for pressure injury prevention has been on repositioning, this study shows that patients with restricted mobility are actually moving quite often. Therefore, it might be appropriate to focus more attention on other pressure injury prevention strategies such as adequate nutrition, appropriate support surfaces and good skin care. © 2013 Wiley Publishing Asia Pty Ltd.

An integrated approach of network-based systems biology, molecular docking, and molecular dynamics approach to unravel the role of existing antiviral molecules against AIDS-associated cancer.

PubMed

Omer, Ankur; Singh, Poonam

2017-05-01

A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS-associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS-associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers.

Differences between novice and experienced caregivers in muscle activity and perceived exertion while repositioning bedridden patients.

PubMed

Daikoku, Rie; Saito, Yayoi

2008-11-01

The aim of this study was to investigate the impact of caregiver knowledge and experience on muscle activity and perceived exertion while repositioning bedridden patients. Subjects were 40- to 65-year-old female caregivers divided into novice and experienced groups. Subjects from both groups performed home-care repositioning techniques on bedridden patients while muscle activity was recorded via electromyogram. Recordings were made from four muscles on the subjects' dominant side: the latissimus dorsi, the biceps brachii, the erector spinae, and the rectus femoris. The subjective burden involved in repositioning was also assessed using the rate of perceived exertion (RPE) and visual analog scales (VAS). Rectus femoris percentage of maximum voluntary contraction (%MVC) values were significantly lower than latissimus dorsi, erector spinae, and biceps brachii values in the novice group. %MVC values from the latissimus dorsi and biceps brachii were significantly higher among the novice group compared to the experienced group. RPE ratings from the novice group were significantly higher than those of the experienced group, and there was a non-significant trend for higher VAS values for the low back, arms, and legs in the novice group compared to the experienced group. Novice caregivers tended to change the patient's position by pulling with the upper limbs without using the lower limbs. In contrast, experienced caregivers exerted less energy by communicating with the patient and utilizing the patient's own movements. They used large, distributed muscle groups that effectively harnessed body mechanics and prevented excess exertion.

Removal and Repositioning of Intracorneal Ring Segments: Improving Corneal Topography and Clinical Outcomes in Keratoconus and Ectasia.

PubMed

Chan, Kahei; Hersh, Peter S

2017-02-01

To evaluate the efficacy of removal and relocation of intracorneal ring segments for improving outcomes in treatment of keratoconus and corneal ectasia. This is a retrospective case series conducted at a cornea and refractive surgery subspecialty practice setting. Patients with previous insertion of 2 intracorneal ring segments underwent surgical removal and repositioning of segments because of unsatisfactory visual and topographic outcomes. The principal outcomes included uncorrected and corrected visual acuities, manifest refraction, topography-derived maximum keratometry (Kmax), inferior-superior topography power difference (I - S), and higher-order aberration profile derived from wavefront analysis. Three patients are presented in this case series. Uncorrected visual acuity improved in all eyes by an average of 2.75 lines. Corrected visual acuity improved in 2 eyes and remained unchanged in 1 eye. Refractive astigmatism decreased in all patients by an average of 2.50 D. Kmax decreased by an average of 1.43 D. All patients had improvement in the I - S value with a mean decrease of 5.13 D. Topography-guided repositioning and/or replacement of corneal ring segments can result in improved topographic, optical, and visual outcomes in patients in whom the initial result is suboptimal. In these cases, a single segment repositioned beneath the cone resulted in an improved outcome. Analysis of corneal topography can guide the surgeon in treatment planning and can suggest patients in whom such an effort will be rewarded with better results.

Misplacement of left-sided double-lumen tubes into the right mainstem bronchus: incidence, risk factors and blind repositioning techniques.

PubMed

Seo, Jeong-Hwa; Bae, Jun-Yeol; Kim, Hyun Joo; Hong, Deok Man; Jeon, Yunseok; Bahk, Jae-Hyon

2015-10-28

Double-lumen endobronchial tubes (DLTs) are commonly advanced into the mainstem bronchus either blindly or by fiberoptic bronchoscopic guidance. However, blind advancement may result in misplacement of left-sided DLTs into the right bronchus. Therefore, incidence, risk factors, and blind repositioning techniques for right bronchial misplacement of left-sided DLTs were investigated. This was an observational cohort study performed on the data depository consecutively collected from patients who underwent intubation of left-sided DLTs for 2 years. Patients' clinical and anatomical characteristics were analyzed to investigate risk factors for DLT misplacements with logistic regression analysis. Moreover, when DLTs were misplaced into the right bronchus, the bronchial tube was withdrawn into the trachea and blindly readvanced without rotation, or with 90° or 180° counterclockwise rotation while the patient's head was turned right. DLTs were inadvertently advanced into the right bronchus in 48 of 1135 (4.2 %) patients. DLT misplacements occurred more frequently in females, in patients of short stature or with narrow trachea and bronchi, and when small-sized DLTs were used. All of these factors were significantly inter-correlated each other (P < 0.001). In 40 of the 48 (83.3 %) patients, blind repositioning was successful. Smaller left-sided DLTs were more frequently misplaced into the right mainstem bronchus than larger DLTs. Moreover, we were usually able to reposition the misplaced DLTs into the left bronchus by using the blind techniques. ClinicalTrials.gov Identifier: NCT01371773.

Does prone repositioning before posterior fixation produce greater lordosis in lateral lumbar interbody fusion (LLIF)?

PubMed

Yson, Sharon C; Sembrano, Jonathan N; Santos, Edward R G; Luna, Jeffrey T P; Polly, David W

2014-10-01

Retrospective comparative radiographic review. To determine if lateral to prone repositioning before posterior fixation confers additional operative level lordosis in lateral lumbar interbody fusion (LLIF) procedures. In a review of 56 consecutive patients who underwent LLIF, there was no statistically significant change in segmental lordosis from lateral to prone once a cage is in place. The greatest lordosis increase was observed after cage insertion. We reviewed 56 consecutive patients who underwent LLIF in the lateral position followed by posterior fixation in the prone position. Eighty-eight levels were fused. Disk space angle was measured on intraoperative C-arm images, and change in operative level segmental lordosis brought about by each of the following was determined: (1) cage insertion, (2) prone repositioning, and (3) posterior instrumentation. Paired t test was used to determine significance (α=0.05). Mean lordosis improvement brought about by cage insertion was 2.6 degrees (P=0.00005). There was a 0.1 degree mean lordosis change brought about by lateral to prone positioning (P=0.47). Mean lordosis improvement brought about by posterior fixation, including rod compression, was 1.0 degree (P=0.03). In LLIF procedures, the largest increase in operative level segmental lordosis is brought about by cage insertion. Further lordosis may be gained by placing posterior fixation, including compressive maneuvers. Prone repositioning after cage placement does not produce any incremental lordosis change. Therefore, posterior fixation may be performed in the lateral position without compromising operative level sagittal alignment.

Structure based mechanism of the Ca(2+)-induced release of coelenterazine from the Renilla binding protein.

PubMed

Stepanyuk, Galina A; Liu, Zhi-Jie; Vysotski, Eugene S; Lee, John; Rose, John P; Wang, Bi-Cheng

2009-02-15

The crystal structure of the Ca(2+)-loaded coelenterazine-binding protein from Renilla muelleri in its apo-state has been determined at resolution 1.8 A. Although calcium binding hardly affects the compact scaffold and overall fold of the structure before calcium addition, there are easily discerned shifts in the residues that were interacting with the coelenterazine and a repositioning of helices, to expose a cavity to the external solvent. Altogether these changes offer a straightforward explanation for how following the addition of Ca(2+), the coelenterazine could escape and become available for bioluminescence on Renilla luciferase. A docking computation supports the possibility of a luciferase-binding protein complex. c) 2008 Wiley-Liss, Inc.

Electromagnetic Tracking Navigation to Guide Radiofrequency Ablation (RFA) of a Lung Tumor

PubMed Central

Amalou, Hayet; Wood, Bradford J.

2013-01-01

Radiofrequency ablation (RFA) may be an option for patients with lung tumors who have unresectable disease and are not suitable for available palliative modalities. RFA electrode positioning may take several attempts, necessitating multiple imaging acquisitions or continuous use of CT (Computed Tomography). Electromagnetic tracking utilizes miniature sensors integrated with RFA equipment to guide tools in real-time, while referencing to pre-procedure imaging. This technology was demonstrated successfully during a lung tumor ablation, and was more accurate at targeting the tumor, compared to traditional freehand needle insertion. It is possible, although speculative and anecdotal, that more accuracy could prevent unnecessary repositioning punctures and decrease radiation exposure. Electromagnetic tracking has theoretical potential to benefit minimally invasive interventions. PMID:23207535

Electromagnetic navigated positioning of the maxilla after Le Fort I osteotomy in preclinical orthognathic surgery cases.

PubMed

Berger, Moritz; Nova, Igor; Kallus, Sebastian; Ristow, Oliver; Eisenmann, Urs; Freudlsperger, Christian; Seeberger, Robin; Hoffmann, Jürgen; Dickhaus, Hartmut

2017-03-01

Inaccuracies in orthognathic surgery can be caused during face-bow registration, model surgery on plaster models, and intermaxillary splint manufacturing. Electromagnetic (EM) navigation is a promising method for splintless digitized maxillary positioning. After performing Le Fort I osteotomy on 10 plastic skulls, the target position of the maxilla was guided by an EM navigation system. Specially implemented software illustrated the target position by real-time multistage colored three-dimensional imaging. Accuracy was determined by using pre- and postoperative cone beam computed tomography. The high accuracy of the EM system was underlined by the fact that it had a navigated maxilla position discrepancy of only 0.4 mm, which was verified by postoperative cone beam computed tomography. This preclinical study demonstrates a precise digitized approach for splintless maxillary repositioning after Le Fort I osteotomy. The accuracy and intuitive illustration of the introduced EM navigation system is promising for potential daily use in orthognathic surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of Intraoperative Computed Tomography for Revisional Procedures in Patients with Complex Maxillofacial Trauma

PubMed Central

Singh, Mansher; Ricci, Joseph A.

2015-01-01

Background: In patients with panfacial fractures and distorted anatomic landmarks of zygomatic and orbital complex, there is a risk of zygomaticomaxillary complex (ZMC) malpositioning even with the best efforts for surgical repair. This results in increased number of additional procedures to achieve accurate positioning. Methods: We describe the usage of intraoperative C-arm cone-beam computed tomographic (CT) scan for ZMC malpositioning in a representative patient with panfacial fractures. Results: We have successfully used intraoperative CT scan for ZMC malpositioning in 3 patients. The representative patient had ZMC malposition after the initial attempt of surgical repair without any intraoperative imaging. On using intraoperative CT scan during the next attempt, we were able to reposition the ZMC accurately. Conclusions: Intraoperative CT scan might improve the accuracy of ZMC positioning and decrease the chances of potential additional surgeries. In patients with distorted anatomical landmarks and panfacial fractures, it can be especially helpful toward correcting ZMC malposition. PMID:26301152

Digital Mammography with a Mosaic of CCD-Arrays

NASA Technical Reports Server (NTRS)

Jalink, Antony, Jr. (Inventor); McAdoo, James A. (Inventor)

1996-01-01

The present invention relates generally to a mammography device and method and more particularly to a novel digital mammography device and method to detect microcalcifications of precancerous tissue. A digital mammography device uses a mosaic of electronic digital imaging arrays to scan an x-ray image. The mosaic of arrays is repositioned several times to expose different portions of the image, until the entire image is scanned. The data generated by the arrays during each exposure is stored in a computer. After the final exposure, the computer combines data of the several partial images to produce a composite of the original x-ray image. An aperture plate is used to reduce scatter and the overall exposure of the patient to x-rays. The novelty of this invention is that it provides a digital mammography device with large field coverage, high spatial resolution, scatter rejection, excellent contrast characteristics and lesion detectability under clinical conditions. This device also shields the patient from excessive radiation, can detect extremely small calcifications and allows manipulation and storage of the image.

Computer-aided drug discovery.

PubMed

Bajorath, Jürgen

2015-01-01

Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

Aesthetic management of gingival recession by root biomodification with carbon dioxide laser and subepithelial connective tissue graft with lateral repositioned flap technique

PubMed Central

Rastogi, Pavitra Kumar; Lal, Nand; Garg, Nimit; Anand, Vishal; Singhal, Rameshwari

2012-01-01

Localised gingival recessions continue to represent an important aesthetic condition requiring treatment in periodontics. Various techniques have been tried to treat exposed root surfaces to improve aesthetics with high percentage of success and minimal discomfort. Root biomodification is done to improve the predictability of these procedures. This clinical report describes periodontal plastic procedure involving subepithelial connective tissue graft with lateral repositioned flap technique and root biomodification with CO2 laser for the management of gingival recession. PMID:22778454

Software and resources for computational medicinal chemistry

PubMed Central

Liao, Chenzhong; Sitzmann, Markus; Pugliese, Angelo; Nicklaus, Marc C

2011-01-01

Computer-aided drug design plays a vital role in drug discovery and development and has become an indispensable tool in the pharmaceutical industry. Computational medicinal chemists can take advantage of all kinds of software and resources in the computer-aided drug design field for the purposes of discovering and optimizing biologically active compounds. This article reviews software and other resources related to computer-aided drug design approaches, putting particular emphasis on structure-based drug design, ligand-based drug design, chemical databases and chemoinformatics tools. PMID:21707404

Chloroquine inhibits hepatocellular carcinoma cell growth in vitro and in vivo

PubMed Central

HU, TAO; LI, PEI; LUO, ZHONGGUANG; CHEN, XIAOYU; ZHANG, JINGYANG; WANG, CHUNYAO; CHEN, PING; DONG, ZIMING

2016-01-01

Recently, chloroquine (CQ) has been widely used to improve the efficacy of different chemotherapy drugs to treat tumors. However, the effects of single treatment of CQ on liver cancer have not been investigated. In the present study, we examined the effects of CQ on the growth and viability of liver cancer cells in vitro and in vivo, and revealed that CQ treatment triggered G0/G1 cell cycle arrest, induced DNA damage and apoptosis in a dose- and time-dependent manner in liver cancer cells. Moreover, administration of CQ to tumor-bearing mice suppressed the tumor growth in an orthotopic xenograft model of liver cancer. These findings extend our understanding and suggest that CQ could be repositioned as a treatment option for liver cancer as a single treatment or in combination. PMID:26530158

Networking Hospital ePrescribing: A Systemic View of Digitalization of Medicines' Use in England.

PubMed

Lichtner, Valentina; Hibberd, Ralph; Cornford, Tony

2016-01-01

Medicine management is at the core of hospital care and digitalization of prescribing and administration of medicines is often the focus of attention of health IT programs. This may be conveyed to the public in terms of the elimination of paper-based drug charts and increased readability of doctors' prescriptions. Based on analysis of documents about hospital medicines supply and use (including systems' implementation) in the UK, in this conceptual paper electronic prescribing and administration are repositioned as only one aspect of an important wider transformation in medicine management in hospital settings, involving, for example, procurement, dispensing, auditing, waste management, research and safety vigilance. Approaching digitalization from a systemic perspective has the potential to uncover the wider implications of this transformation for patients, the organization and the wider health care system.

Femoral articular shape and geometry. A three-dimensional computerized analysis of the knee.

PubMed

Siu, D; Rudan, J; Wevers, H W; Griffiths, P

1996-02-01

An average, three-dimensional anatomic shape and geometry of the distal femur were generated from x-ray computed tomography data of five fresh asymptomatic cadaver knees using AutoCAD (AutoDesk, Sausalito, CA), a computer-aided design and drafting software. Each femur model was graphically repositioned to a standardized orientation using a series of alignment templates and scaled to a nominal size of 85 mm in mediolateral and 73 mm in anteroposterior dimensions. An average generic shape of the distal femur was synthesized by combining these pseudosolid models and reslicing the composite structure at different elevations using clipping and smoothing techniques in interactive computer graphics. The resulting distal femoral geometry was imported into a computer-aided manufacturing system, and anatomic prototypes of the distal femur were produced. Quantitative geometric analyses of the generic femur in the coronal and transverse planes revealed definite condylar camber (3 degrees-6 degrees) and toe-in (8 degrees-10 degrees) with an oblique patellofemoral groove (15 degrees) with respect to the mechanical axis of the femur. In the sagittal plane, each condyle could be approximated by three concatenated circular arcs (anterior, distal, and posterior) with slope continuity and a single arc for the patellofemoral groove. The results of this study may have important implications in future femoral prosthesis design and clinical applications.

Guidance and Control System for a Satellite Constellation

NASA Technical Reports Server (NTRS)

Bryson, Jonathan Lamar; Cox, James; Mays, Paul Richard; Neidhoefer, James Christian; Ephrain, Richard

2010-01-01

A distributed guidance and control algorithm was developed for a constellation of satellites. The system repositions satellites as required, regulates satellites to desired orbits, and prevents collisions. 1. Optimal methods are used to compute nominal transfers from orbit to orbit. 2. Satellites are regulated to maintain the desired orbits once the transfers are complete. 3. A simulator is used to predict potential collisions or near-misses. 4. Each satellite computes perturbations to its controls so as to increase any unacceptable distances of nearest approach to other objects. a. The avoidance problem is recast in a distributed and locally-linear form to arrive at a tractable solution. b. Plant matrix values are approximated via simulation at each time step. c. The Linear Quadratic Gaussian (LQG) method is used to compute perturbations to the controls that will result in increased miss distances. 5. Once all danger is passed, the satellites return to their original orbits, all the while avoiding each other as above. 6. The delta-Vs are reasonable. The controller begins maneuvers as soon as practical to minimize delta-V. 7. Despite the inclusion of trajectory simulations within the control loop, the algorithm is sufficiently fast for available satellite computer hardware. 8. The required measurement accuracies are within the capabilities of modern inertial measurement devices and modern positioning devices.

Computer-assisted virtual technology in intracapsular condylar fracture with two resorbable long-screws.

PubMed

Wang, W H; Deng, J Y; Zhu, J; Li, M; Xia, B; Xu, B

2013-03-01

Our aim was to fix intracapsular condylar fractures (ICF) with two resorbable long screws using preoperative computer-assisted virtual technology. From February 2008 to July 2011, 19 patients with ICF were treated with two resorbable long screws. Preoperatively we took panoramic radiographs and spiral computed tomography (CT). Depending on their digital imaging and communications in medicine (DICOM) data, the dislocated condylar segments were restored using the SimPlant Pro™ software, version 11.04. The mean (SD) widths of the condylar head and neck from lateral to medial were 19.01 (1.28)mm and 13.84 (1.13)mm, respectively. In all patients, the mandibles and the ICF seen intraoperatively corresponded with the preoperative three-dimensional and virtual reposition. All patients were followed up for 6-46 months (mean 21). Occlusion and mouth opening had been restored completely in all but one patient, and absolute anatomical reduction was also achieved in most cases. Computer-assisted virtual technology plays an important part in the diagnosis of ICF, as well as in its preoperative design. Fixation with only two resorbable long screws is an effective and reliable method for fixing ICF. Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

μ-PIV measurements of the ensemble flow fields surrounding a migrating semi-infinite bubble.

PubMed

Yamaguchi, Eiichiro; Smith, Bradford J; Gaver, Donald P

2009-08-01

Microscale particle image velocimetry (μ-PIV) measurements of ensemble flow fields surrounding a steadily-migrating semi-infinite bubble through the novel adaptation of a computer controlled linear motor flow control system. The system was programmed to generate a square wave velocity input in order to produce accurate constant bubble propagation repeatedly and effectively through a fused glass capillary tube. We present a novel technique for re-positioning of the coordinate axis to the bubble tip frame of reference in each instantaneous field through the analysis of the sudden change of standard deviation of centerline velocity profiles across the bubble interface. Ensemble averages were then computed in this bubble tip frame of reference. Combined fluid systems of water/air, glycerol/air, and glycerol/Si-oil were used to investigate flows comparable to computational simulations described in Smith and Gaver (2008) and to past experimental observations of interfacial shape. Fluorescent particle images were also analyzed to measure the residual film thickness trailing behind the bubble. The flow fields and film thickness agree very well with the computational simulations as well as existing experimental and analytical results. Particle accumulation and migration associated with the flow patterns near the bubble tip after long experimental durations are discussed as potential sources of error in the experimental method.

Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes.

PubMed

Pinto, Erika G; da Costa-Silva, Thais A; Tempone, Andre Gustavo

2014-09-01

Considering the limited and toxic therapeutic arsenal available for visceral leishmaniasis (VL), the drug repositioning approach could represent a promising tool to the introduction of alternative therapies. Histamine H1-receptor antagonists are drugs belonging to different therapeutic classes, including antiallergics and anxyolitics. In this work, we described for the first time the activity of H1-antagonists against L. (L.) infantum and their potential effectiveness in an experimental hamster model. The evaluation against promastigotes demonstrated that chlorpheniramine, cinnarizine, hydroxyzine, ketotifen, loratadine, quetiapine and risperidone exerted a leishmanicidal effect against promastigotes, with IC50 values in the range of 13-84μM. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21μM. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229μM. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50mg/kg by intraperitoneal route (i.p.) and at 100mg/kg by oral route to L. infantum-infected hamsters, but showed lack of effectiveness in both regimens, as detected by real time PCR. The liposomal formulation was administered by i.p. route at 3mg/kg for eight days and reduced the parasite burden to 54% in liver when compared to untreated group; no improvement was observed in the spleen of infected hamsters. Cinnarizine is the first antihistaminic drug with antileishmanial activity and could be used as scaffold for drug design studies for VL. Copyright © 2014 Elsevier B.V. All rights reserved.

Correlation of clinical predictions and surgical results in maxillary superior repositioning.

PubMed

Tabrizi, Reza; Zamiri, Barbad; Kazemi, Hamidreza

2014-05-01

This is a prospective study to evaluate the accuracy of clinical predictions related to surgical results in subjects who underwent maxillary superior repositioning without anterior-posterior movement. Surgeons' predictions according to clinical (tooth show at rest and at the maximum smile) and cephalometric evaluation were documented for the amount of maxillary superior repositioning. Overcorrection or undercorrection was documented for every subject 1 year after the operations. Receiver operating characteristic curve test was used to find a cutoff point in prediction errors and to determine positive predictive value (PPV) and negative predictive value. Forty subjects (14 males and 26 females) were studied. Results showed a significant difference between changes in the tooth show at rest and at the maximum smile line before and after surgery. Analysis of the data demonstrated no correlation between the predictive data and the surgical results. The incidence of undercorrection (25%) was more common than overcorrection (7.5%). The cutoff point for errors in predictions was 5 mm for tooth show at rest and 15 mm at the maximum smile. When the amount of the presurgical tooth show at rest was more than 5 mm, 50.5% of clinical predictions did not match the clinical results (PPV), and 75% of clinical predictions showed the same results when the tooth show was less than 5 mm (negative predictive value). When the amount of presurgical tooth shown in the maximum smile line was more than 15 mm, 75% of clinical predictions did not match with clinical results (PPV), and 25% of the predictions had the same results because the tooth show at the maximum smile was lower than 15 mm. Clinical predictions according to the tooth show at rest and at the maximum smile have a poor correlation with clinical results in maxillary superior repositioning for vertical maxillary excess. The risk of errors in predictions increased when the amount of superior repositioning of the maxilla increased. Generally, surgeons have a tendency to undercorrect rather than overcorrect, although clinical prediction is an original guideline for surgeons, and it may be associated with variable clinical results.

Impact of treatment on health-related quality of life in patients with posterior canal benign paroxysmal positional vertigo.

PubMed

Lopez-Escamez, Jose A; Gamiz, Maria J; Fernandez-Perez, Antonio; Gomez-Fiñana, Manuel; Sanchez-Canet, Isabel

2003-07-01

To determine the impact of the particle repositioning maneuver on posterior canal benign paroxysmal positional vertigo-related quality of life using the Medical Outcomes Study 36-Item Short Form Health Survey and the Dizziness Handicap Inventory Short Form. Prospective, consecutive new cases of posterior canal benign paroxysmal positional vertigo. Ambulatory, primary referral hospital. Forty individuals with posterior canal benign paroxysmal positional vertigo were investigated. The diagnosis was made on the basis of the history of recurrent sudden crisis of vertigo and positional-induced nystagmus during the Dix-Hallpike test. All patients were treated by a single particle repositioning maneuver, and relapses were investigated at Days 7 and 30 posttreatment. Percentage of patients with negative Dix-Hallpike test after treatment, scores obtained on the 36-Item Short Form Health Survey and Dizziness Handicap Inventory Short Form before and 30 days after treatment. DHT was found negative in 76% (28 of 37) individuals at 30 days. The eight scales of the 36-Item Short Form Health Survey had a good internal consistency reliability (Cronbach's alpha > 0.7) in patients with posterior canal benign paroxysmal positional vertigo. The average standardized score for each 36-Item Short Form Health Survey scale was compared with the reference population normative data, showing differences with norms for all scales, except for Vitality. After particle repositioning maneuver, patients scored closer to norms, and Social Function and Mental Health scores were significantly higher than the scores obtained before the particle repositioning maneuver (p < 0.05). Dizziness Handicap Inventory Short Form total score significantly decreased from 18.05 +/- 9.91 (mean +/- standard deviation) at the first day to 9.54 +/- 9.94 at 30 days (p < 0.001). All 36-Item Short Form Health Survey scale scores were correlated significantly with Dizziness Handicap Inventory Short Form total scores at 30 days after treatment. Posterior canal benign paroxysmal positional vertigo has a significant impact on health-related quality of life, and patients experienced a decrease in quality of life as compared with norms. The particle repositioning maneuver improves health-related quality of life in posterior canal benign paroxysmal positional vertigo.

Factors contributing to evidence-based pressure ulcer prevention. A cross-sectional study.

PubMed

Sving, Eva; Idvall, Ewa; Högberg, Hans; Gunningberg, Lena

2014-05-01

Implementation of evidence-based care for pressure ulcer prevention is lacking. As the hospital organization is complex, more knowledge is needed to understand how nursing care in this area can be improved. The present study investigated the associations between variables on different levels in the healthcare setting (patient, unit, hospital) and the documentation of (1) risk assessment and (2) skin assessment within 24h of admission, the use of (3) pressure-reducing mattresses and (4) planned repositioning in bed. A cross-sectional study. One university hospital and one general hospital. Geriatric (n=8), medical (n=24) and surgical (n=19) units. All adult patients (>17 years), in total 825, were included. A one-day prevalence study was conducted using the methodology specified by the European Pressure Ulcer Advisory Panel, together with the established methods used by the Collaborative Alliance for Nursing Outcomes. Independent variables were patient characteristics, hospital type, unit type, nurse staffing and workload. Dependent variables were documented risk and skin assessment within 24h of admission, pressure-reducing mattresses and planned repositioning in bed. The data were analysed with Logistic regression using the Generalized Estimating Equation (GEE) approach. Patients at risk of developing pressure ulcers (Braden<17) had higher odds of having risk assessment documented, and of receiving pressure-reducing mattresses and planned repositioning. Patients at the general hospital were less likely to have risk and skin assessment documented and to receive pressure-reducing mattresses. On the other hand, planned repositioning was more likely to be used at the general hospital. When total hours of nursing care was lower, patients had higher odds of having pressure-reducing mattresses but were less likely to have planned repositioning. Patient characteristics (high age and risk score) and hospital type were associated with pressure ulcer prevention. Surprisingly, nurse staffing played only a minor role. Leaders in healthcare organizations should establish routines on different levels that support evidence-based pressure ulcer prevention, and registered nurses need to assume responsibility for bedside care. Copyright © 2013 Elsevier Ltd. All rights reserved.

[The importance of vestibular evoked myogenic potentials for the assessment of the otolith function in the patients presenting with benign paroxysmal positional vertigo].

PubMed

Kunel'skaya, N L; Baybakova, E V; Guseva, A L; Chugunova, M A; Manaenkova, E A

The objective of the present study was to evaluate the otolith function in the patients presenting with idiopathic benign paroxysmal positional vertigo (pBPPV) attributable to the occlusion of the posterior semicircular canal (PSCC) of the inner ear with the use of vestibular evoked myogenic potentials (VEMP). Cervical (cVEMP) and ocular VEMP (oVEMP) were measured in 34 patients with idiopathic pBPPV before and 7 days after the treatment by means of reposition maneuvers. The results of the repeated Dix-Hallpike test performed 7 days after the repositioning maneuver were negative in 27 patients and positive in 7 patients. There was no statistically significant difference in the amplitude of cervical VEMP between the healthy and affected ears either before or after the repositioning treatment. The measurement of oVEMP revealed a reduction of the response amplitude on the affected side. The average values of the plnl on the healthy side were 12.84±1.09 and those on the affected side 4.62±0.69 (p<0,05). The successful repositioning treatment resulted in a significant increase of the oVEMP amplitude on the affected side (p<0,05). In the patients presenting with the persistent symptoms of pBPPV, the repositioning maneuvers did not cause an appreciable increase in the amplitude of oVEMP on the affected side (p<0.05). The results of the present study give evidence that pBPPV of the posterior semicircular canal is associated with the impairment of the function of the receptor structures of the utriculus and the preserved function of the succulus as suggested by the reduction of the oVEMP amplitude and clinically significant asymmetry of ocular VEMP on the affected side with intact cervical VEMP on both sides. The successful treatment of pBPPV of PSCC with the use of the liberatory maneuver results in the increase of the oVEMP amplitude on the affected side increases while the response asymmetry between both sides significantly decreases which indicates the repair of the utriculus otolith function.

Analysis of cache for streaming tape drive

NASA Technical Reports Server (NTRS)

Chinnaswamy, V.

1993-01-01

A tape subsystem consists of a controller and a tape drive. Tapes are used for backup, data interchange, and software distribution. The backup operation is addressed. During a backup operation, data is read from disk, processed in CPU, and then sent to tape. The processing speeds of a disk subsystem, CPU, and a tape subsystem are likely to be different. A powerful CPU can read data from a fast disk, process it, and supply the data to the tape subsystem at a faster rate than the tape subsystem can handle. On the other hand, a slow disk drive and a slow CPU may not be able to supply data fast enough to keep a tape drive busy all the time. The backup process may supply data to tape drive in bursts. Each burst may be followed by an idle period. Depending on the nature of the file distribution in the disk, the input stream to the tape subsystem may vary significantly during backup. To compensate for these differences and optimize the utilization of a tape subsystem, a cache or buffer is introduced in the tape controller. Most of the tape drives today are streaming tape drives. A streaming tape drive goes into reposition when there is no data from the controller. Once the drive goes into reposition, the controller can receive data, but it cannot supply data to the tape drive until the drive completes its reposition. A controller can also receive data from the host and send data to the tape drive at the same time. The relationship of cache size, host transfer rate, drive transfer rate, reposition, and ramp up times for optimal performance of the tape subsystem are investigated. Formulas developed will also show the advantages of cache watermarks to increase the streaming time of the tape drive, maximum loss due to insufficient cache, tradeoffs between cache and reposition times and the effectiveness of cache on a streaming tape drive due to idle times or interruptions due in host transfers. Several mathematical formulas are developed to predict the performance of the tape drive. Some examples are given illustrating the usefulness of these formulas. Finally, a summary and some conclusions are provided.

Ketamine for Treatment-Resistant Unipolar Depression

PubMed Central

Mathew, Sanjay J.; Shah, Asim; Lapidus, Kyle; Clark, Crystal; Jarun, Noor; Ostermeyer, Britta; Murrough, James W.

2013-01-01

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD. PMID:22303887

First in Human Clinical Trial of Ultrasonic Propulsion of Kidney Stones.

PubMed

Harper, Jonathan D; Cunitz, Bryan W; Dunmire, Barbrina; Lee, Franklin C; Sorensen, Mathew D; Hsi, Ryan S; Thiel, Jeff; Wessells, Hunter; Lingeman, James E; Bailey, Michael R

2016-04-01

Ultrasonic propulsion is a new technology using focused ultrasound energy applied transcutaneously to reposition kidney stones. We report what are to our knowledge the findings from the first human investigational trial of ultrasonic propulsion toward the applications of expelling small stones and dislodging large obstructing stones. Subjects underwent ultrasonic propulsion while awake without sedation in clinic, or during ureteroscopy while anesthetized. Ultrasound and a pain questionnaire were completed before, during and after propulsion. The primary outcome was to reposition stones in the collecting system. Secondary outcomes included safety, controllable movement of stones and movement of stones less than 5 mm and 5 mm or greater. Adverse events were assessed weekly for 3 weeks. Kidney stones were repositioned in 14 of 15 subjects. Of the 43 targets 28 (65%) showed some level of movement while 13 (30%) were displaced greater than 3 mm to a new location. Discomfort during the procedure was rare, mild, brief and self-limited. Stones were moved in a controlled direction with more than 30 fragments passed by 4 of the 6 subjects who had previously undergone a lithotripsy procedure. The largest stone moved was 10 mm. One patient experienced pain relief during treatment of a large stone at the ureteropelvic junction. In 4 subjects a seemingly large stone was determined to be a cluster of small passable stones after they were moved. Ultrasonic propulsion was able to successfully reposition stones and facilitate the passage of fragments in humans. No adverse events were associated with the investigational procedure. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Valgus osteotomy and repositioning and fixation with a dynamic hip screw and a 135º single-angled barrel plate for un-united and neglected femoral neck fractures.

PubMed

Gupta, Sameer; Kukreja, Sunil; Singh, Vivek

2014-04-01

To review the outcome of 60 patients who underwent valgus subtrochanteric osteotomy and its repositioning for un-united and neglected femoral neck fractures. 60 patients (mean age, 35 years) underwent valgus subtrochanteric osteotomy and repositioning of the osteotomy and fixation with a dynamic hip screw and a 135° single-angled barrel plate for closed un-united femoral neck fractures after failed internal fixation (n=27) or neglected (>3 weeks) fractures (n=33). The most common fracture type was transcervical (n=48), followed by subcapital (n=6) and basal (n=6). All patients had displaced femoral neck fractures (Garden types 3 and 4). According to the Pauwel angle, 45 fractures were type 2 (30º-70º) and 15 were type 3 (>70º). Patients were followed up for a mean of 3.5 (range, 2-7.5) years. The mean Pauwel angle of the fracture was corrected from 65° (range, 50°-89°) to 26° (range, 25°-28°). Bone union was achieved in 56 patients after a mean of 3.9 (range, 3-5.5) months. The mean Harris hip score improved from 65 to 87.5. Outcome was excellent in 30 patients, good in 24, and poor in 6. Four of the patients developed avascular necrosis; 2 of whom nonetheless achieved a good outcome. Valgus osteotomy and repositioning and fixation with a dynamic hip screw and a 135° single-angled barrel plate was effective treatment for un-united and neglected femoral neck fractures.

Spatial Positioning of All 24 Chromosomes in the Lymphocytes of Six Subjects: Evidence of Reproducible Positioning and Spatial Repositioning following DNA Damage with Hydrogen Peroxide and Ultraviolet B

PubMed Central

Kandukuri, Lakshmi; Quadri, Ameer; Becerra, Victor; Simpson, Joe Leigh

2015-01-01

The higher-order organization of chromatin is well-established, with chromosomes occupying distinct positions within the interphase nucleus. Chromatin is susceptible to, and constantly assaulted by both endogenous and exogenous threats. However, the effects of DNA damage on the spatial topology of chromosomes are hitherto, poorly understood. This study investigates the organization of all 24 human chromosomes in lymphocytes from six individuals prior to- and following in-vitro exposure to genotoxic agents: hydrogen peroxide and ultraviolet B. This study is the first to report reproducible distinct hierarchical radial organization of chromosomes with little inter-individual differences between subjects. Perturbed nuclear organization was observed following genotoxic exposure for both agents; however a greater effect was observed for hydrogen peroxide including: 1) More peripheral radial organization; 2) Alterations in the global distribution of chromosomes; and 3) More events of chromosome repositioning (18 events involving 10 chromosomes vs. 11 events involving 9 chromosomes for hydrogen peroxide and ultraviolet B respectively). Evidence is provided of chromosome repositioning and altered nuclear organization following in-vitro exposure to genotoxic agents, with notable differences observed between the two investigated agents. Repositioning of chromosomes following genotoxicity involved recurrent chromosomes and is most likely part of the genomes inherent response to DNA damage. The variances in nuclear organization observed between the two agents likely reflects differences in mobility and/or decondensation of chromatin as a result of differences in the type of DNA damage induced, chromatin regions targeted, and DNA repair mechanisms. PMID:25756782

Spatial positioning of all 24 chromosomes in the lymphocytes of six subjects: evidence of reproducible positioning and spatial repositioning following DNA damage with hydrogen peroxide and ultraviolet B.

PubMed

Ioannou, Dimitrios; Kandukuri, Lakshmi; Quadri, Ameer; Becerra, Victor; Simpson, Joe Leigh; Tempest, Helen G

2015-01-01

The higher-order organization of chromatin is well-established, with chromosomes occupying distinct positions within the interphase nucleus. Chromatin is susceptible to, and constantly assaulted by both endogenous and exogenous threats. However, the effects of DNA damage on the spatial topology of chromosomes are hitherto, poorly understood. This study investigates the organization of all 24 human chromosomes in lymphocytes from six individuals prior to- and following in-vitro exposure to genotoxic agents: hydrogen peroxide and ultraviolet B. This study is the first to report reproducible distinct hierarchical radial organization of chromosomes with little inter-individual differences between subjects. Perturbed nuclear organization was observed following genotoxic exposure for both agents; however a greater effect was observed for hydrogen peroxide including: 1) More peripheral radial organization; 2) Alterations in the global distribution of chromosomes; and 3) More events of chromosome repositioning (18 events involving 10 chromosomes vs. 11 events involving 9 chromosomes for hydrogen peroxide and ultraviolet B respectively). Evidence is provided of chromosome repositioning and altered nuclear organization following in-vitro exposure to genotoxic agents, with notable differences observed between the two investigated agents. Repositioning of chromosomes following genotoxicity involved recurrent chromosomes and is most likely part of the genomes inherent response to DNA damage. The variances in nuclear organization observed between the two agents likely reflects differences in mobility and/or decondensation of chromatin as a result of differences in the type of DNA damage induced, chromatin regions targeted, and DNA repair mechanisms.

Treatment of mandibular symphyseal fracture combined with dislocated intracapsular condylar fractures.

PubMed

Xu, Xiaofeng; Shi, Jun; Xu, Bing; Dai, Jiewen; Zhang, Shilei

2015-03-01

To evaluate the treatment methods of mandibular symphyseal fracture combined with dislocated intracapsular condylar fractures (MSF&DICF) and to compare the effect of different treatment methods of condylar fractures. Twenty-eight patients with MSF&DICF were included in this study. Twenty-two sites were treated by open reduction, and all the medial condylar fragments were fixed with titanium screws; whereas the other 22 sites underwent close treatment. The surgical effect between these 2 groups was compared based on clinical examination and radiographic examination results. Seventeen of 22 condyle fractures were repositioned in the surgery group, whereas 4 of 22 condyle fractures were repositioned in the close treatment group. Statistical difference was observed between these 2 groups (P < 0.01). Functional outcomes of the patients treated in the surgical treatment group also were better than those in the close treatment group. The dislocated intracapsular condyle fractures should be treated by surgical reduction with the maintenance of the attachment of lateral pterygoid muscle, which is beneficial to repositioning the dislocated condyle to its original physiological position, to closure of the mandibular lingual gap, to restore the mandibular width.

Pressure ulcers and lateral rotation beds: a case study.

PubMed

Russell, Teresa; Logsdon, Angela

2003-05-01

During a 6-month period, the WOC nurses at a 500-bed medical treatment facility noticed the development of nosocomial pressure ulcers on the sacrum, occiput, and heel areas of patients who were placed on lateral rotation specialty beds because they had pulmonary disorders. Measures were taken to address the problem by repositioning the patients and through a staff education program. Repositioning included repositioning the patient's head every 2 hours, thorough skin assessments every 2 hours, and ensuring that the patient's heels were subject to zero pressure. Staff education centered on the importance of using a risk assessment tool (the Braden scale) and understanding the clinical uses for lateral rotation beds. During the subsequent 6 months, the incidence of hospital-acquired pressure ulcers decreased by 52%. Efforts to further decrease the number of pressure ulcers related to the use of lateral rotation beds continue. Issues such as length of stay on the bed and the appropriateness of manufacturer's guidelines still need to be addressed at this facility. This case study highlights the potential issues associated with lateral rotation beds and identifies the need for further research.

Customerizing the clinical laboratory. Repositioning for enhanced service and a competitive advantage.

PubMed

Schuler, R S

1989-01-01

The call for excellence has never been louder, especially in the health-care industry. This call typically means increased service, i.e., faster, more accurate and, of course, friendlier service--all easier said than done, but qualities that make enhanced customer service so powerful. The excellent companies are learning that because it is so difficult to customerize, few competitors do so. Therefore, by devoting the time and effort necessary for customerization, they can move ahead of their competitors. But surpassing competitors by excellent service can be done inside of companies as well as outside. All units and departments have customers. The key to customerization inside is finding out what your customers want and behaving accordingly. The results go beyond enhanced customer satisfaction. They also include enhanced energy levels, reduced turnover, increased pride, and greater creativity for the newly customerized department. All it takes is an understanding of and dedication to customerization. Repositioning the existing department is critical to the success of any attempt to customerize. This article thoroughly describes customerization and the entire process of repositioning the clinical laboratory. One will not occur without the other.

The clinical outcomes of surgical management of anterior chamber migration of a dexamethasone implant (Ozurdex®).

PubMed

Kang, Hyunseung; Lee, Min Woo; Byeon, Suk Ho; Koh, Hyoung Jun; Lee, Sung Chul; Kim, Min

2017-09-01

Our purpose was to describe the clinical course, and individualized management approaches, of patients with migration of a dexamethasone implant into the anterior chamber. This was a retrospective review of four patients with seven episodes of anterior chamber migration of a dexamethasone implant. After 924 intravitreal dexamethasone injections, anterior migration of the implant occurred in four eyes of four patients (0.43%). All four eyes were pseudophakic: one eye had a posterior chamber intraocular lens in the capsular bag but in a post-laser posterior capsulotomy state, two eyes had a sulcus intraocular lens (IOL), and one eye had an iris-fixated retropupillary IOL. All eyes had a prior vitrectomy and no lens capsule. The time interval from injection to detection of the implant migration ranged from 2 to 6 weeks. Of the four eyes with corneal edema, only one eye required a corneal transplantation, although it was unclear whether the implant migration was the direct cause of the corneal decompensation because the patient had a history of bullous keratopathy resulting from an extended history of uveitis. All patients underwent surgical intervention: two patients with a repositioning procedure, and the other two patients with removal due to repeated episodes, although surgical removal was not always necessary to reverse the corneal complications. In our study, not all patients required surgical removal of the implants. Repositioning the implant back into the vitreous cavity may be considered as an option in cases involving the first episode with no significant corneal endothelial decompensation. Considering potential anterior segment complications and the loss of drug effectiveness together, an individualized approach is recommended to obtain the best treatment outcomes and to minimize the risk of corneal complications.

Novel opportunities for computational biology and sociology in drug discovery☆

PubMed Central

Yao, Lixia; Evans, James A.; Rzhetsky, Andrey

2013-01-01

Current drug discovery is impossible without sophisticated modeling and computation. In this review we outline previous advances in computational biology and, by tracing the steps involved in pharmaceutical development, explore a range of novel, high-value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy–industry links for scientific and human benefit. Attention to these opportunities could promise punctuated advance and will complement the well-established computational work on which drug discovery currently relies. PMID:20349528

Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective.

PubMed

Perales-Patón, Javier; Piñeiro-Yañez, Elena; Tejero, Héctor; López-Casas, Pedro P; Hidalgo, Manuel; Gómez-López, Gonzalo; Al-Shahrour, Fátima

2017-01-01

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death among solid malignancies. Unfortunately, PDAC lethality has not substantially decreased over the past 20 years. This aggressiveness is related to the genomic complexity and heterogeneity of PDAC, but also to the absence of an effective screening for the detection of early-stage tumors and a lack of efficient therapeutic options. Therefore, there is an urgent need to improve the arsenal of anti-PDAC drugs for an effective treatment of these patients. Patient-derived xenograft (PDX) mouse models represent a promising strategy to personalize PDAC treatment, offering a bench testing of candidate treatments and helping to select empirical treatments in PDAC patients with no therapeutic targets. Moreover, bioinformatics-based approaches have the potential to offer systematic insights into PDAC etiology predicting putatively actionable tumor-specific genomic alterations, identifying novel biomarkers and generating disease-associated gene expression signatures. This review focuses on recent efforts to individualize PDAC treatments using PDX models. Additionally, we discuss the current understanding of the PDAC genomic landscape and the putative druggable targets derived from mutational studies. PDAC molecular subclassifications and gene expression profiling studies are reviewed as well. Finally, latest bioinformatics methodologies based on somatic variant detection and prioritization, in silico drug response prediction, and drug repositioning to improve the treatment of advanced PDAC tumors are also covered. © 2017 S. Karger AG, Basel.

In vitro additive interaction between ketoconazole and antimony against intramacrophage Leishmania (Leishmania) amazonensis amastigotes.

PubMed

Nunes, Débora Cristina de Oliveira; Bispo-da-Silva, Luiz Borges; Napolitano, Danielle Reis; Costa, Mônica Soares; Figueira, Márcia Moura Nunes Rocha; Rodrigues, Renata Santos; Rodrigues, Veridiana de Melo; Yoneyama, Kelly Aparecida Geraldo

2017-01-01

Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. The currently available treatments for this disease are expensive, present high toxicity and are associated to difficulties of healing and parasite resistance. Therefore, the development of strategies for leishmaniasis treatment is indispensable and includes reposition of existing drugs, as well as drug combination therapy. The aim of this study was to assess the nature of ketoconazole and antimony association on the cytotoxic effect against Leishmania (Leishmania) amazonensis amastigotes. The calculated mean sum of fractional 50% inhibitory concentration ([Formula: see text]ΣFIC50) was 2.54 and 1.43 for free and intracellular amastigotes, respectively, values that suggest an additive interaction between ketoconazole and antimony concerning to Leishmania toxicity only in the intramacrophage parasite form. Despite the clinical efficacy of ketoconazole-antimony combination has been shown in the literature, our study is the first to describe the nature of ketoconazole-antimony interaction against L. (L.) amazonensis amastigotes. Moreover, our results point out the need for future in vivo studies to confirm the nature of ketoconazole-antimony interaction and also to determine possible effective dosage regimens related to ketoconazole administration in association with the optimal lower dose of antimony.

[Possibilities and limits of topical hydrocortisone therapy. Experiences in general practice].

PubMed

Mussler, H

1983-12-01

Dermatologists in practice as well as in hospitals use similar specific methods of treatment. This is to the advantage of the patients. Critical review of patient's records will clearly establish the pros and cons of drugs in specific indications. Over the past years the steroids had a very expansive development but it seems, that the use of mono- or difluorized corticosteroids becomes more and more critical. This is not only due to local side-effects; but also due to the increased rate of resorption, especially in children with extended skin deseases. In this connection the question of repositioning of hydrocortison-preparations, drugs of the so called first generation, becomes again of interest. This report is based on experiences and results with Sanatison, a hydrocortison ointment in the therapy of patients with a variety of different skin disorders. This seems to be of more interest than the treatment of numerous patients with the same disorder. The purpose of this study was to find out, to what extend the hydrocortison ointment Sanatison 1/3% and 1% resp., which is associated to a substantial lesser amount of skin damage, can cure or ameliorate different dermatoses.

Novel opportunities for computational biology and sociology in drug discovery

PubMed Central

Yao, Lixia

2009-01-01

Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

[The Significance of Early Reposition in Patients with Visible Malposition of the Upper Ankle Joint].

PubMed

Wohlrath, B; Schweigkofler, U; Barzen, S; Heinz, S M; Schmidt-Horlohé, K; Hoffmann, R

2016-12-01

Background: Protracted dislocation of the upper ankle joint can lead to substantial damage to the surrounding soft tissue, possibly followed by local complications and longer hospitalisation. Although reposition is usually easy to conduct, it is commonly recommended that this should only be performed by an experienced specialist, as long as there is no neurovascular restriction. There are however no exact data or studies on this problem. The aim of the present study is to examine whether early reposition is of benefit for subsequent treatment. Methods: Retrospective study of all patients in a supra-regional trauma centre during the period from January 2009 to July 2015, with either prehospital reposition of the ankle joint because of visible malposition or documented visible malposition on arrival at hospital. Patients with relevant concomitant injuries elsewhere were excluded. Data on the duration of dislocation were matched with diagnostic findings at the time of hospital admission, the kind of primary care, local complications and the time of hospitalisation, using linear regression analysis and ANOVA calculations. Results: Of a total of 391 patients with a dislocation or a fracture dislocation of the ankle joint within this period, 132 fulfilled the inclusion criteria. These patients were divided into 5 groups on the basis of the time of dislocation. Time to reposition was less than one hour for 39 patients, between one and two hours for 29 patients, between two and six hours for 41 patients, between six and 24 hours for 13 patients and more than 24 hours for 10 patients, all with a visible dislocation. The results on admission showed a significant increase in skin bruises and tension bullae with increasing time of dislocation. A longer time of dislocation was associated with more two stage surgical procedures with external fixators and a decreasing number of single stage procedures. While there was immediate definitive treatment of 79.5 % of the patients in the first group, this figure decreased continuously to 10.0 % in the last group. The number of local complications increased significantly in every group with the duration of dislocation. In particular, the incidence of severe swelling, wound healing disorders, skin necrosis and the need for revision surgery and plastic reconstruction exhibit a significant linear increase within the groups (p < 0.05). The incidence of severe swelling rose from 10.3 % in the first group, to 31.0 % in the second group, to 100 % in the last group. The incidence of wound healing disorders rose from 7.7 to 13.8 to 80 % and the incidence of skin necrosis from 2.6 to 3.5 to 30.0 %. The duration of hospitalisation also exhibited a significant linear increase with group affiliation (p < 0.001), from 8.3 days in the first group to 12.5 days in the second group and 30.5 days in the last group. Conclusion: This study shows the importance of conducting reposition of the ankle joint as soon as possible if there is visible malposition, in order to avoid local complications and longer hospitalisation. If there is visible malposition of the ankle joint, the best procedure is immediate - ideally prehospital - reposition and in-axis splinting, in order to preserve soft tissue. Georg Thieme Verlag KG Stuttgart · New York.

Interposition of a connective tissue graft or a collagen matrix to enhance wound stability - an experimental study in dogs.

PubMed

Burkhardt, Rino; Ruiz Magaz, Vanessa; Hämmerle, Christoph H F; Lang, Niklaus P

2016-04-01

The aim of this study was to evaluate the role of a connective tissue graft (CTG) or a collagen matrix (CM) interpositioned between flaps and non-shedding hard surfaces on wound stability. Sixty bone dehiscence defects were prepared in five Beagle dogs. Three treatments were performed in 12 sites per dog: (1) repositioned flaps were sutured onto instrumented dentin surfaces (control), (2) repositioning of flaps with an interpositioned CTG and (3) repositioning of flaps with the application of a CM. To allow postoperative healing with n = 5 for 1, 3, 7 and 14 days before evaluation, the sutures were removed, incision lines retraced and tensile forces applied to the flaps. The minimum magnitude of forces required to detach the flaps from the wound bed was recorded. After 1 week of healing, 6 N had to be applied to disrupt flaps from their wound bed in the CTG group. In the control group, a similar magnitude of resistance was achieved after 2 weeks (6.1 N). Flap resistance to tearing was highest in the CTG group (maximum 9.1 N) 2 weeks postoperatively. On the third postoperative day, the mean tearing forces of all groups differed significantly, displaying a 50% lower resistance to tearing in the CM compared to the CTG group. In comparison, flap resistance to tearing forces established earlier and in higher magnitude in sites with an interpositioned CTG than in flaps repositioned on dentin or CM. Application of a CTG, sutured to a non-shedding hard surface, significantly increased flap resistance to tearing when applying disrupting forces compared to controls. A less pronounced effect was achieved by interpositioning of a CM. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An early shoulder repositioning program in birth-related brachial plexus injury: a pilot study of the Sup-ER protocol.

PubMed

Verchere, Cynthia; Durlacher, Kim; Bellows, Doria; Pike, Jeffrey; Bucevska, Marija

2014-06-01

Birth-related brachial plexus injury (BRBPI) occurs in 1.2/1,000 births in British Columbia. Even in children with "good" recovery, external rotation (ER) and supination (Sup) are often weaker, and permanent skeletal imbalance ensues. A preventive early infant shoulder passive repositioning program was created using primarily a novel custom splint holding the affected arm in full ER and Sup: the Sup-ER splint. The details of the splint and the shoulder repositioning program evolved with experience over several years. This study reviews the first 4 years. A retrospective review of BCCH patients managed with the Sup-ER protocol from 2008 to 2011 compared their recovery scores to matched historical controls selected from our database by two independent reviewers. The protocol was initiated in 18 children during the study period. Six were excluded due to the following: insufficient data points, non-compliance, late splint initiation, and loss to follow-up. Of the 12 matches, the Sup-ER group final score at 2 years was better than controls by 1.18 active movement scale (AMS) points (p = 0.036) in Sup and 0.96 AMS points in ER (but not statistically significant (p = 0.13)). Unexpectedly, but importantly, during the study period, zero subjects were assessed to have the active functional criteria to indicate brachial plexus reconstruction, where previously we operated on 13 %. Early application of passive shoulder repositioning into Sup and ER may improve outcomes in function of the arm in infants with BRBPI. A North American multi-site randomized control trial has been approved and has started recruitment.

Cervicocephalic kinesthetic sensibility and postural balance in patients with nontraumatic chronic neck pain--a pilot study.

PubMed

Palmgren, Per J; Andreasson, Daniel; Eriksson, Magnus; Hägglund, Andreas

2009-06-30

Although cervical pain is widespread, most victims are only mildly and occasionally affected. A minority, however, suffer chronic pain and/or functional impairments. Although there is abundant literature regarding nontraumatic neck pain, little focuses on diagnostic criteria. During the last decade, research on neck pain has been designed to evaluate underlying pathophysiological mechanisms, without noteworthy success. Independent researchers have investigated postural balance and cervicocephalic kinesthetic sensibility among patients with chronic neck pain, and have (in most cases) concluded the source of the problem is a reduced ability in the neck's proprioceptive system. Here, we investigated cervicocephalic kinesthetic sensibility and postural balance among patients with nontraumatic chronic neck pain. Ours was a two-group, observational pilot study of patients with complaints of continuous neck pain during the 3 months prior to recruitment. Thirteen patients with chronic neck pain of nontraumatic origin were recruited from an institutional outpatient clinic. Sixteen healthy persons were recruited as a control group. Cervicocephalic kinesthetic sensibility was assessed by exploring head repositioning accuracy and postural balance was measured with computerized static posturography. Parameters of cervicocephalic kinesthetic sensibility were not reduced. However, in one of six test movements (flexion), global repositioning errors were significantly larger in the experimental group than in the control group (p < .05). Measurements did not demonstrate any general impaired postural balance, and varied substantially among participants in both groups. In patients with nontraumatic chronic neck pain, we found statistically significant global repositioning errors in only one of six test movements. In this cohort, we found no evidence of impaired postural balance.Head repositioning accuracy and computerized static posturography are imperfect measures of functional proprioceptive impairments. Validity of (and procedures for using) these instruments demand further investigation. Current Controlled Trials ISRCTN96873990.

Use of a Behavioural Pain Scale to assess pain in ventilated, unconscious and/or sedated patients.

PubMed

Young, Jeanne; Siffleet, Jo; Nikoletti, Sue; Shaw, Thérèse

2006-02-01

Current empirical evidence supports claims that pain in sedated, unconscious Intensive Care Unit (ICU) patients is underrated and under-treated. Given the severity of ICU patients' illness pain management, whilst important, may not be considered a priority and therefore can be easily overlooked. The aim of this study was to validate the Behavioural Pain Scale (BPS) for the assessment of pain in critically ill patients by evaluating facial expressions, upper limb movements and compliance with mechanical ventilation. A prospective, descriptive repeated measures study design was used to assess the validity and reliability of the BPS for assessing pain in critically ill patients undergoing routine painful (repositioning) and non-painful (eye care) procedures. An average of 73% of BPS scores increased (indicating pain) after patients were repositioned, as opposed to 14% after eye care. This increase was statistically significant for repositioning (p < 0.003) but not for eye care (p > 0.3). The odds of an increase in BPS between pre- and post-procedure assessments was more than 25 times higher for repositioning compared with eye care (p < 0.0001), after controlling for analgesics and sedatives. The BPS was found to be a valid and reliable tool in the assessment of pain in the unconscious sedated patient. Results also highlighted that traditional pain indicators, such as fluctuations in haemodynamic parameters, are not always an accurate measure for the assessment of pain in unconscious patients and as such more objective pain assessment measures are essential. Finally, further validation of the BPS and identification of other painful routine procedures is needed to enhance pain management delivery for unconscious patients.

Subchromosomal karyotype evolution in Equidae.

PubMed

Musilova, P; Kubickova, S; Vahala, J; Rubes, J

2013-04-01

Equidae is a small family which comprises horses, African and Asiatic asses, and zebras. Despite equids having diverged quite recently, their karyotypes underwent rapid evolution which resulted in extensive differences among chromosome complements in respective species. Comparative mapping using whole-chromosome painting probes delineated genome-wide chromosome homologies among extant equids, enabling us to trace chromosome rearrangements that occurred during evolution. In the present study, we performed subchromosomal comparative mapping among seven Equidae species, representing the whole family. Region-specific painting and bacterial artificial chromosome probes were used to determine the orientation of evolutionarily conserved segments with respect to centromere positions. This allowed assessment of the configuration of all fusions occurring during the evolution of Equidae, as well as revealing discrepancies in centromere location caused by centromere repositioning or inversions. Our results indicate that the prevailing type of fusion in Equidae is centric fusion. Tandem fusions of the type telomere-telomere occur almost exclusively in the karyotype of Hartmann's zebra and are characteristic of this species' evolution. We revealed inversions in segments homologous to horse chromosomes 3p/10p and 13 in zebras and confirmed inversions in segments 4/31 in African ass, 7 in horse and 8p/20 in zebras. Furthermore, our mapping results suggested that centromere repositioning events occurred in segments homologous to horse chromosomes 7, 8q, 10p and 19 in the African ass and an element homologous to horse chromosome 16 in Asiatic asses. Centromere repositioning in chromosome 1 resulted in three different chromosome types occurring in extant species. Heterozygosity of the centromere position of this chromosome was observed in the kiang. Other subtle changes in centromere position were described in several evolutionary conserved chromosomal segments, suggesting that tiny centromere repositioning or pericentric inversions are quite frequent in zebras and asses.

Precision measurements of the RSA method using a phantom model of hip prosthesis.

PubMed

Mäkinen, Tatu J; Koort, Jyri K; Mattila, Kimmo T; Aro, Hannu T

2004-04-01

Radiostereometric analysis (RSA) has become one of the recommended techniques for pre-market evaluation of new joint implant designs. In this study we evaluated the effect of repositioning of X-ray tubes and phantom model on the precision of the RSA method. In precision measurements, we utilized mean error of rigid body fitting (ME) values as an internal control for examinations. ME value characterizes relative motion among the markers within each rigid body and is conventionally used to detect loosening of a bone marker. Three experiments, each consisting of 10 double examinations, were performed. In the first experiment, the X-ray tubes and the phantom model were not repositioned between one double examination. In experiments two and three, the X-ray tubes were repositioned between one double examination. In addition, the position of the phantom model was changed in experiment three. Results showed that significant differences could be found in 2 of 12 comparisons when evaluating the translation and rotation of the prosthetic components. Repositioning procedures increased ME values mimicking deformation of rigid body segments. Thus, ME value seemed to be a more sensitive parameter than migration values in this study design. These results confirmed the importance of standardized radiographic technique and accurate patient positioning for RSA measurements. Standardization and calibration procedures should be performed with phantom models in order to avoid unnecessary radiation dose of the patients. The present model gives the means to establish and to follow the intra-laboratory precision of the RSA method. The model is easily applicable in any research unit and allows the comparison of the precision values in different laboratories of multi-center trials.

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs

PubMed Central

Rasheed, Saima; Sánchez, Sara S.; Yousuf, Sammer; Honoré, Stella M.; Choudhary, M. Iqbal

2018-01-01

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover “new targets” for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents. PMID:29300762

The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Zhai, Weiwei; Lim, Tony Kiat-Hon; Zhang, Tong; Phang, Su-Ting; Tiang, Zenia; Guan, Peiyong; Ng, Ming-Hwee; Lim, Jia Qi; Yao, Fei; Li, Zheng; Ng, Poh Yong; Yan, Jie; Goh, Brian K.; Chung, Alexander Yaw-Fui; Choo, Su-Pin; Khor, Chiea Chuen; Soon, Wendy Wei-Jia; Sung, Ken Wing-Kin; Foo, Roger Sik-Yin; Chow, Pierce Kah-Hoe

2017-02-01

Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.

Development and positioning reliability of a TMS coil holder for headache research.

PubMed

Chronicle, Edward P; Pearson, A Jane; Matthews, Cheryl

2005-01-01

Accurate and reproducible coil positioning is important for headache research using transcranial magnetic stimulation protocols. We aimed to design a transcranial magnetic stimulation coil holder and demonstrate reliability of test-retest coil positioning. A coil holder was developed and manufactured according to three principles of stability, durability, and three-dimensional positional accuracy. Reliability of coil positioning was assessed by stimulating over the motor cortex of four neurologically normal subjects and recording finger muscle responses, both at a test phase and a retest phase several hours later. In all four subjects, repositioning of the transcranial magnetic stimulation coil solely on the basis of coil holder coordinates was accurate to within 2 mm. The coil holder demonstrated good test-retest reliability of coil positioning, and is thus a promising tool for transcranial magnetic stimulation-based headache research, particularly studies of prophylactic drug effect where several laboratory visits with identical coil positioning are necessary.

Discovering Synergistic Drug Combination from a Computational Perspective.

PubMed

Ding, Pingjian; Luo, Jiawei; Liang, Cheng; Xiao, Qiu; Cao, Buwen; Li, Guanghui

2018-03-30

Synergistic drug combinations play an important role in the treatment of complex diseases. The identification of effective drug combination is vital to further reduce the side effects and improve therapeutic efficiency. In previous years, in vitro method has been the main route to discover synergistic drug combinations. However, many limitations of time and resource consumption lie within the in vitro method. Therefore, with the rapid development of computational models and the explosive growth of large and phenotypic data, computational methods for discovering synergistic drug combinations are an efficient and promising tool and contribute to precision medicine. It is the key of computational methods how to construct the computational model. Different computational strategies generate different performance. In this review, the recent advancements in computational methods for predicting effective drug combination are concluded from multiple aspects. First, various datasets utilized to discover synergistic drug combinations are summarized. Second, we discussed feature-based approaches and partitioned these methods into two classes including feature-based methods in terms of similarity measure, and feature-based methods in terms of machine learning. Third, we discussed network-based approaches for uncovering synergistic drug combinations. Finally, we analyzed and prospected computational methods for predicting effective drug combinations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases

PubMed Central

Chernomoretz, Ariel; Agüero, Fernán

2016-01-01

Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature. PMID:26735851

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets.

PubMed

Harris, Lynne M; Monsell, Katelyn R; Noulin, Florian; Famodimu, M Toyin; Smargiasso, Nicolas; Damblon, Christian; Horrocks, Paul; Merrick, Catherine J

2018-03-01

G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum , which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs. Copyright © 2018 American Society for Microbiology.

A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases.

PubMed

Berenstein, Ariel José; Magariños, María Paula; Chernomoretz, Ariel; Agüero, Fernán

2016-01-01

Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature.

Computational drug discovery

PubMed Central

Ou-Yang, Si-sheng; Lu, Jun-yan; Kong, Xiang-qian; Liang, Zhong-jie; Luo, Cheng; Jiang, Hualiang

2012-01-01

Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field. PMID:22922346

Impact of computational structure-based methods on drug discovery.

PubMed

Reynolds, Charles H

2014-01-01

Structure-based drug design has become an indispensible tool in drug discovery. The emergence of structure-based design is due to gains in structural biology that have provided exponential growth in the number of protein crystal structures, new computational algorithms and approaches for modeling protein-ligand interactions, and the tremendous growth of raw computer power in the last 30 years. Computer modeling and simulation have made major contributions to the discovery of many groundbreaking drugs in recent years. Examples are presented that highlight the evolution of computational structure-based design methodology, and the impact of that methodology on drug discovery.

Cone-Beam Computed Tomography–Guided Positioning of Laryngeal Cancer Patients with Large Interfraction Time Trends in Setup and Nonrigid Anatomy Variations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gangsaas, Anne, E-mail: a.gangsaas@erasmusmc.nl; Astreinidou, Eleftheria; Quint, Sandra

2013-10-01

Purpose: To investigate interfraction setup variations of the primary tumor, elective nodes, and vertebrae in laryngeal cancer patients and to validate protocols for cone beam computed tomography (CBCT)-guided correction. Methods and Materials: For 30 patients, CBCT-measured displacements in fractionated treatments were used to investigate population setup errors and to simulate residual setup errors for the no action level (NAL) offline protocol, the extended NAL (eNAL) protocol, and daily CBCT acquisition with online analysis and repositioning. Results: Without corrections, 12 of 26 patients treated with radical radiation therapy would have experienced a gradual change (time trend) in primary tumor setup ≥4more » mm in the craniocaudal (CC) direction during the fractionated treatment (11/12 in caudal direction, maximum 11 mm). Due to these trends, correction of primary tumor displacements with NAL resulted in large residual CC errors (required margin 6.7 mm). With the weekly correction vector adjustments in eNAL, the trends could be largely compensated (CC margin 3.5 mm). Correlation between movements of the primary and nodal clinical target volumes (CTVs) in the CC direction was poor (r{sup 2}=0.15). Therefore, even with online setup corrections of the primary CTV, the required CC margin for the nodal CTV was as large as 6.8 mm. Also for the vertebrae, large time trends were observed for some patients. Because of poor CC correlation (r{sup 2}=0.19) between displacements of the primary CTV and the vertebrae, even with daily online repositioning of the vertebrae, the required CC margin around the primary CTV was 6.9 mm. Conclusions: Laryngeal cancer patients showed substantial interfraction setup variations, including large time trends, and poor CC correlation between primary tumor displacements and motion of the nodes and vertebrae (internal tumor motion). These trends and nonrigid anatomy variations have to be considered in the choice of setup verification protocol and planning target volume margins. eNAL could largely compensate time trends with minor prolongation of fraction time.« less

Combined pressure regulator and shutoff valve

NASA Technical Reports Server (NTRS)

Koch, E. F. (Inventor)

1974-01-01

A remotely operable pressure regulator and shutoff valve particularly suited for achieving high resolution and flow control, and positive shutoff is described. The valve is characterized by a spring-loaded ball coaxially aligned with a fluid port to be sealed, a spring-loaded pintle extended through the port into engagement with the ball, for controlling the position, a spring-loaded diaphragm for controlling the position of the pintle, and an axially displaceable spring supported by a movable stop which, in turn, is repositioned by a selectively operable stepper motor. Thus, the pressure-response characteristics for the valve can be varied through a selective repositioning of the stop.

Transcriptional repression mediated by repositioning of genes to the nuclear lamina.

PubMed

Reddy, K L; Zullo, J M; Bertolino, E; Singh, H

2008-03-13

Nuclear compartmentalization seems to have an important role in regulating metazoan genes. Although studies on immunoglobulin and other loci have shown a correlation between positioning at the nuclear lamina and gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM), and tested the consequences of such repositioning on gene activity in mouse fibroblasts. Here, using three-dimensional DNA-immunoFISH, we demonstrate repositioning of chromosomal regions to the nuclear lamina that is dependent on breakdown and reformation of the nuclear envelope during mitosis. Moreover, tethering leads to the accumulation of lamin and INM proteins, but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Finally, we use targeted adenine methylation (DamID) to show that, as is the case for our model system, inactive immunoglobulin loci at the nuclear periphery are contacted by INM and lamina proteins. We propose that these molecular interactions may be used to compartmentalize and to limit the accessibility of immunoglobulin loci to transcription and recombination factors.

Heliocentric phasing performance of electric sail spacecraft

NASA Astrophysics Data System (ADS)

Mengali, Giovanni; Quarta, Alessandro A.; Aliasi, Generoso

2016-10-01

We investigate the heliocentric in-orbit repositioning problem of a spacecraft propelled by an Electric Solar Wind Sail. Given an initial circular parking orbit, we look for the heliocentric trajectory that minimizes the time required for the spacecraft to change its azimuthal position, along the initial orbit, of a (prescribed) phasing angle. The in-orbit repositioning problem can be solved using either a drift ahead or a drift behind maneuver and, in general, the flight times for the two cases are different for a given value of the phasing angle. However, there exists a critical azimuthal position, whose value is numerically found, which univocally establishes whether a drift ahead or behind trajectory is superior in terms of flight time it requires for the maneuver to be completed. We solve the optimization problem using an indirect approach for different values of both the spacecraft maximum propulsive acceleration and the phasing angle, and the solution is then specialized to a repositioning problem along the Earth's heliocentric orbit. Finally, we use the simulation results to obtain a first order estimate of the minimum flight times for a scientific mission towards triangular Lagrangian points of the Sun-[Earth+Moon] system.

Robotic active positioning for magnetic resonance-guided high-intensity focused ultrasound

NASA Astrophysics Data System (ADS)

Xiao, Xu; Huang, Zhihong; Volovick, Alexander; Melzer, Andreas

2012-11-01

Magnetic resonance (MR) guided High-intensity focused ultrasound (HIFU) is a noninvasive method producing thermal necrosis and cavitation at the position of tumors with high accuracy. Because the typical size of the high-intensity focused ultrasound focus are much smaller than the targeted tumor or other tissues, multiple sonications and focus repositioning become necessary for HIFU treatment. In order to reach a much wider range, manual repositioning or using MR compatible mechanical actuators could be used. The repositioning technique is a time consuming procedure because it needs a series of MR imaging to detect the transducer and markers preplaced on the mechanical devices. We combined an active tracking technique into the MR guided HIFU system. In this work, the robotic system used is the MR-compatible robotics from InnoMotion{trade mark, serif} (IBSMM, Engineering spol. s r.o. / Ltd, Czech) which is originally designed for MR-guided needle biopsy. The precision and positioning speed of the combined robotic HIFU system are evaluated in this study. Compared to the existing MR guided HIFU systems, the combined robotic system with active tracking techniques provides a potential that allows the HIFU treatment to operate in a larger spatial range and with a faster speed.

[Supracondylar humerus fracture in childhood--an efficacy study. Results of a multicenter study by the Pediatric Traumatology Section of the German Society of Trauma Surgery--II: Costs and effectiveness of the treatment].

PubMed

von Laer, L; Günter, S M; Knopf, S; Weinberg, Annelie M

2002-03-01

The following are the results and conclusions of a retrospective research study done on 886 patients with supracondylar fractures of the humerus. The study evaluates how effective the treatment procedures of the fractures are. The patients' fractures were categorized into four groups. It made it easier to differentiate between dislocated and undislocated fractures (see part I Weinberg A et al.). The following parameters were established to evaluate the treatment procedures and to create relevancy to the final outcome depending on the degree of difficulty of the fractures: Length of hospitalization, amount of repositioning procedures (including if an open or closed procedure was needed), amount of post repositioning procedures and the recommended change of therapy, method of retention and fixation, necessary metal removal, amount of check ups needed. The amount of x-ray exams could not be established due to insufficient documentation. The study showed a rather random pattern regarding length of hospitalization and the amount of check ups especially among type I and II patients. Open versus closed repositioning procedures did not seem to be advantageous. The implanted wires did not prevent infections. It just increased the treatment procedure by another hospitalization and anesthesia to remove the implanted wires. Physical therapy was not necessary and was only prescribed in cases of prolonged immobilization. The results of this study generated consequences regarding treatment procedures and developed a more efficient treatment protocol: Type I and II (dislocated and undislocated fractures in one plane) will be treated conservatively on an out-patient basis. Type I in a cast. Type II in a blount or plaster cast with flexed angle between 100 degrees and 130 degrees. Type III an IV (dislocated and undislocated fractures in two or three planes) will be treated if possible with a closed repositioning procedure. Otherwise a close repositioning procedure will be necessary and followed with some kind of KD-osteosynthese to capture the fracture. The patient will be hospitalized for a short period. The blount procedure will not be sufficient for this type of fracture. Therapy and procedure will be translated put in a perspective research study.

Graphical User Interface in Art

NASA Astrophysics Data System (ADS)

Gwilt, Ian

This essay discusses the use of the Graphical User Interface (GUI) as a site of creative practice. By creatively repositioning the GUI as a work of art it is possible to challenge our understanding and expectations of the conventional computer interface wherein the icons and navigational architecture of the GUI no longer function as a technological tool. These artistic recontextualizations are often used to question our engagement with technology and to highlight the pivotal place that the domestic computer has taken in our everyday social, cultural and (increasingly), creative domains. Through these works the media specificity of the screen-based GUI can broken by dramatic changes in scale, form and configuration. This can be seen through the work of new media artists who have re-imagined the GUI in a number of creative forms both, within the digital, as image, animation, net and interactive art, and in the analogue, as print, painting, sculpture, installation and performative event. Furthermore as a creative work, the GUI can also be utilized as a visual way-finder to explore the relationship between the dynamic potentials of the digital and the concretized qualities of the material artifact.

A high-content screening of anti-cancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy.

PubMed

Sidarovich, Viktoryia; De Mariano, Marilena; Aveic, Sanja; Pancher, Michael; Adami, Valentina; Gatto, Pamela; Pizzini, Silvia; Pasini, Luigi; Croce, Michela; Parodi, Federica; Cimmino, Flora; Avitabile, Marianna; Emionite, Laura; Cilli, Michele; Ferrini, Silvano; Pagano, Aldo; Capasso, Mario; Quattrone, Alessandro; Tonini, Gian Paolo; Longo, Luca

2018-04-25

Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anti-cancer compounds library. In the primary screening we employed three NB cell lines, grown as 3D multicellular spheroids, which were treated with 10 μM of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in 2D and 3D models. Dose-response curves were then supplemented with the data on side-effects, therapeutic index and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Copyright ©2018, American Association for Cancer Research.

Recent Findings in the Genetics of Blood Pressure: How to Apply in Practice or Is a Moonshot Required?

PubMed

Padmanabhan, Sandosh; Aman, Alisha; Dominiczak, Anna F

2018-06-07

Hypertension is recognised as the biggest contributor to the global burden of disease, but it is controlled in less than a fifth of patients worldwide, despite being relatively easy to detect and the availability of inexpensive safe generic drugs. Blood pressure is regulated by a complex network of physiologic pathways with currently available drugs targeting key receptors or enzymes in the top pathways. Major advances in the dissection of both monogenic and polygenic determinants of blood pressure regulation and variation have not resulted in rapid translation of these discoveries into clinical applications or precision medicine. Uromodulin is an example of a novel gene for hypertension identified from genome-wide association studies, currently the basis of a clinical trial to reposition loop diuretics in hypertension management. Gene-editing studies have established a genome-wide association studies (GWAS) SNP in chromosome 6p24, implicated in six conditions including hypertension, as a distal regulator of the endothelin-1 gene around 3000 base pairs away. Genomics of aldosterone-producing adenomas bring to focus the paradox in genomic medicine where availability of cheap generic drugs may render precision medicine uneconomical. The speed of technology-driven genomic discoveries and the sluggish traditional pathways of drug development and translation need harmonisation to make a timely and early impact on global public health. This requires a directed collaborative effort for which we propose a hypertension moonshot to make a quantum leap in hypertension management and cardiovascular risk reduction by bringing together traditional bioscience, omics, engineering, digital technology and data science.

Computer-Aided Drug Design in Epigenetics

NASA Astrophysics Data System (ADS)

Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

2018-03-01

Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

Computer-Aided Drug Design in Epigenetics

PubMed Central

Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

2018-01-01

Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field. PMID:29594101

21 CFR 870.1110 - Blood pressure computer.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Blood pressure computer. 870.1110 Section 870.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... computer. (a) Identification. A blood pressure computer is a device that accepts the electrical signal from...

21 CFR 870.1110 - Blood pressure computer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Blood pressure computer. 870.1110 Section 870.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... computer. (a) Identification. A blood pressure computer is a device that accepts the electrical signal from...

21 CFR 870.1110 - Blood pressure computer.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Blood pressure computer. 870.1110 Section 870.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... computer. (a) Identification. A blood pressure computer is a device that accepts the electrical signal from...

21 CFR 870.1110 - Blood pressure computer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Blood pressure computer. 870.1110 Section 870.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... computer. (a) Identification. A blood pressure computer is a device that accepts the electrical signal from...

Orthodontic treatment for oral rehabilitation after multiple maxillofacial bone fractures.

PubMed

Nakamura, Yoshiki; Ogino, Tomoko Kuroiwa; Hirashita, Ayao

2008-09-01

We present the orthodontic treatment of a patient with occlusal dysfunction after plastic surgery for multiple maxillofacial bone fractures caused by a traffic accident. The patient had mandibular deviation to the right because of inappropriate repositioning and fixation of the fractured bone and complete avulsion of both mandibular central incisors. The bilateral mandibular incisors, canines, and premolars were also suspected of partial avulsion or alveolar bone fracture. Several tests, including percussion and dental computed tomography, were performed on these teeth to rule out ankylosis and confirm tooth movement. Camouflage orthodontic treatment was carried out with expansion of the maxillary arch, alignment of both arches, and space closure between the mandibular lateral incisors to improve the occlusion. Good occlusion and interdigitation were obtained. Orthodontic treatment is useful for the rehabilitation of occlusal dysfunction caused by multiple maxillofacial bone fractures.

Applying Squeaky-Wheel Optimization Schedule Airborne Astronomy Observations

NASA Technical Reports Server (NTRS)

Frank, Jeremy; Kuerklue, Elif

2004-01-01

We apply the Squeaky Wheel Optimization (SWO) algorithm to the problem of scheduling astronomy observations for the Stratospheric Observatory for Infrared Astronomy, an airborne observatory. The problem contains complex constraints relating the feasibility of an astronomical observation to the position and time at which the observation begins, telescope elevation limits, special use airspace, and available fuel. Solving the problem requires making discrete choices (e.g. selection and sequencing of observations) and continuous ones (e.g. takeoff time and setting up observations by repositioning the aircraft). The problem also includes optimization criteria such as maximizing observing time while simultaneously minimizing total flight time. Previous approaches to the problem fail to scale when accounting for all constraints. We describe how to customize SWO to solve this problem, and show that it finds better flight plans, often with less computation time, than previous approaches.

Seeing is believing: on the use of image databases for visually exploring plant organelle dynamics.

PubMed

Mano, Shoji; Miwa, Tomoki; Nishikawa, Shuh-ichi; Mimura, Tetsuro; Nishimura, Mikio

2009-12-01

Organelle dynamics vary dramatically depending on cell type, developmental stage and environmental stimuli, so that various parameters, such as size, number and behavior, are required for the description of the dynamics of each organelle. Imaging techniques are superior to other techniques for describing organelle dynamics because these parameters are visually exhibited. Therefore, as the results can be seen immediately, investigators can more easily grasp organelle dynamics. At present, imaging techniques are emerging as fundamental tools in plant organelle research, and the development of new methodologies to visualize organelles and the improvement of analytical tools and equipment have allowed the large-scale generation of image and movie data. Accordingly, image databases that accumulate information on organelle dynamics are an increasingly indispensable part of modern plant organelle research. In addition, image databases are potentially rich data sources for computational analyses, as image and movie data reposited in the databases contain valuable and significant information, such as size, number, length and velocity. Computational analytical tools support image-based data mining, such as segmentation, quantification and statistical analyses, to extract biologically meaningful information from each database and combine them to construct models. In this review, we outline the image databases that are dedicated to plant organelle research and present their potential as resources for image-based computational analyses.

Robust diffraction correction method for high-frequency ultrasonic tissue characterization

NASA Astrophysics Data System (ADS)

Raju, Balasundar

2004-05-01

The computation of quantitative ultrasonic parameters such as the attenuation or backscatter coefficient requires compensation for diffraction effects. In this work a simple and accurate diffraction correction method for skin characterization requiring only a single focal zone is developed. The advantage of this method is that the transducer need not be mechanically repositioned to collect data from several focal zones, thereby reducing the time of imaging and preventing motion artifacts. Data were first collected under controlled conditions from skin of volunteers using a high-frequency system (center frequency=33 MHz, BW=28 MHz) at 19 focal zones through axial translation. Using these data, mean backscatter power spectra were computed as a function of the distance between the transducer and the tissue, which then served as empirical diffraction correction curves for subsequent data. The method was demonstrated on patients patch-tested for contact dermatitis. The computed attenuation coefficient slope was significantly (p<0.05) lower at the affected site (0.13+/-0.02 dB/mm/MHz) compared to nearby normal skin (0.2+/-0.05 dB/mm/MHz). The mean backscatter level was also significantly lower at the affected site (6.7+/-2.1 in arbitrary units) compared to normal skin (11.3+/-3.2). These results show diffraction corrected ultrasonic parameters can differentiate normal from affected skin tissues.

About the inevitable compromise between spatial resolution and accuracy of strain measurement for bone tissue: a 3D zero-strain study.

PubMed

Dall'Ara, E; Barber, D; Viceconti, M

2014-09-22

The accurate measurement of local strain is necessary to study bone mechanics and to validate micro computed tomography (µCT) based finite element (FE) models at the tissue scale. Digital volume correlation (DVC) has been used to provide a volumetric estimation of local strain in trabecular bone sample with a reasonable accuracy. However, nothing has been reported so far for µCT based analysis of cortical bone. The goal of this study was to evaluate accuracy and precision of a deformable registration method for prediction of local zero-strains in bovine cortical and trabecular bone samples. The accuracy and precision were analyzed by comparing scans virtually displaced, repeated scans without any repositioning of the sample in the scanner and repeated scans with repositioning of the samples. The analysis showed that both precision and accuracy errors decrease with increasing the size of the region analyzed, by following power laws. The main source of error was found to be the intrinsic noise of the images compared to the others investigated. The results, once extrapolated for larger regions of interest that are typically used in the literature, were in most cases better than the ones previously reported. For a nodal spacing equal to 50 voxels (498 µm), the accuracy and precision ranges were 425-692 µε and 202-394 µε, respectively. In conclusion, it was shown that the proposed method can be used to study the local deformation of cortical and trabecular bone loaded beyond yield, if a sufficiently high nodal spacing is used. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Challenging Intrauterine Contraceptive: In-office Hysteroscopic Approach.

PubMed

Di Spiezio Sardo, Attilio; da Cunha Vieira, Mariana; Scognamiglio, Marianna; Zizolfi, Brunella; Nappi, Carmine; de Angelis, Carlo

2016-01-01

To describe 3 cases of misplaced or retained Intrauterine Contraceptive (IUC) that were successfully resolved by hysteroscopy performed in an ambulatory setting using miniaturized electrosurgical and mechanical operative instruments. Step-by-step description of the technique using slides, pictures, and video (educative video) (Canadian Task Force classification III). Misplaced or retained IUC may be related to several causes; incorrect insertion is the leading cause. In these cases, patients may complain of abnormal bleeding, pelvic pain, or pregnancy or they may remain asymptomatic. When a displaced IUC is suspected, transvaginal ultrasonography is the primary investigation followed by radiography in cases in which the IUC is not seen within the uterus. Additional imaging such as computed tomographic scanning or magnetic resonance imaging may be needed. Hysteroscopy represents the gold standard for diagnostic clarification and management of a dislocated or embedded IUC. The hysteroscopic approach of the 3 cases was the following: removal of a partially perforating IUD in the cesarean scar pouch, repositioning of a dislocated IUS in the isthmocele, and removal of an embedded IUS in the cornual area. The procedures were performed in an ambulatory setting using a 5-mm continuous flow hysteroscope and vaginoscopic approach without any analgesia and/or anesthesia. The alternate use of mechanical and electrosurgical 5F instruments allowed us to separate the IUC from the myometrial uterine wall, respecting the healthy myometrium and without causing significant patient discomfort or complications. The possibility of using miniaturized electrosurgical and mechanical instruments with small-diameter hysteroscopes offers the possibility of an effective, safe, cost-efficient, and well-tolerated removal or repositioning of a misplaced or retained IUC. This minimally invasive approach can be performed in an office setting to avoid more invasive and traumatic approaches. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

Using Free Computational Resources to Illustrate the Drug Design Process in an Undergraduate Medicinal Chemistry Course

ERIC Educational Resources Information Center

Rodrigues, Ricardo P.; Andrade, Saulo F.; Mantoani, Susimaire P.; Eifler-Lima, Vera L.; Silva, Vinicius B.; Kawano, Daniel F.

2015-01-01

Advances in, and dissemination of, computer technologies in the field of drug research now enable the use of molecular modeling tools to teach important concepts of drug design to chemistry and pharmacy students. A series of computer laboratories is described to introduce undergraduate students to commonly adopted "in silico" drug design…

The importance of employing computational resources for the automation of drug discovery.

PubMed

Rosales-Hernández, Martha Cecilia; Correa-Basurto, José

2015-03-01

The application of computational tools to drug discovery helps researchers to design and evaluate new drugs swiftly with a reduce economic resources. To discover new potential drugs, computational chemistry incorporates automatization for obtaining biological data such as adsorption, distribution, metabolism, excretion and toxicity (ADMET), as well as drug mechanisms of action. This editorial looks at examples of these computational tools, including docking, molecular dynamics simulation, virtual screening, quantum chemistry, quantitative structural activity relationship, principal component analysis and drug screening workflow systems. The authors then provide their perspectives on the importance of these techniques for drug discovery. Computational tools help researchers to design and discover new drugs for the treatment of several human diseases without side effects, thus allowing for the evaluation of millions of compounds with a reduced cost in both time and economic resources. The problem is that operating each program is difficult; one is required to use several programs and understand each of the properties being tested. In the future, it is possible that a single computer and software program will be capable of evaluating the complete properties (mechanisms of action and ADMET properties) of ligands. It is also possible that after submitting one target, this computer-software will be capable of suggesting potential compounds along with ways to synthesize them, and presenting biological models for testing.

Influence of impression technique and material on the accuracy of multiple implant impressions.

PubMed

Wöstmann, Bernd; Rehmann, Peter; Balkenhol, Markus

2008-01-01

This study aimed to analyze the influence of impression technique (pick-up versus reposition) and material on the accuracy of the working cast. Sixty impressions were made with 3 materials from a master cast with 4 XiVE implants. The changes in the implant axis direction, rotation, and 3-dimensional shift were assessed. The pick-up technique showed significantly (P < .05, U test) lower values for axis direction and 3D shift but higher values for rotation than the reposition technique. The differences between the materials were not significant (P > .05, H test). It can be concluded that the impression technique-in contrast to the impression material-has a significant influence on transfer accuracy.

Computer-Aided Drug Discovery: Molecular Docking of Diminazene Ligands to DNA Minor Groove

ERIC Educational Resources Information Center

Kholod, Yana; Hoag, Erin; Muratore, Katlynn; Kosenkov, Dmytro

2018-01-01

The reported project-based laboratory unit introduces upper-division undergraduate students to the basics of computer-aided drug discovery as a part of a computational chemistry laboratory course. The students learn to perform model binding of organic molecules (ligands) to the DNA minor groove with computer-aided drug discovery (CADD) tools. The…

Computational 3D structures of drug-targeting proteins in the 2009-H1N1 influenza A virus

NASA Astrophysics Data System (ADS)

Du, Qi-Shi; Wang, Shu-Qing; Huang, Ri-Bo; Chou, Kuo-Chen

2010-01-01

The neuraminidase (NA) and M2 proton channel of influenza virus are the drug-targeting proteins, based on which several drugs were developed. However these once powerful drugs encountered drug-resistant problem to the H5N1 and H1N1 flu. To address this problem, the computational 3D structures of NA and M2 proteins of 2009-H1N1 influenza virus were built using the molecular modeling technique and computational chemistry method. Based on the models the structure features of NA and M2 proteins were analyzed, the docking structures of drug-protein complexes were computed, and the residue mutations were annotated. The results may help to solve the drug-resistant problem and stimulate designing more effective drugs against 2009-H1N1 influenza pandemic.

Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics.

PubMed

Fukunishi, Yoshifumi; Mashimo, Tadaaki; Misoo, Kiyotaka; Wakabayashi, Yoshinori; Miyaki, Toshiaki; Ohta, Seiji; Nakamura, Mayu; Ikeda, Kazuyoshi

2016-01-01

Computer-aided drug design is still a state-of-the-art process in medicinal chemistry, and the main topics in this field have been extensively studied and well reviewed. These topics include compound databases, ligand-binding pocket prediction, protein-compound docking, virtual screening, target/off-target prediction, physical property prediction, molecular simulation and pharmacokinetics/pharmacodynamics (PK/PD) prediction. Message and Conclusion: However, there are also a number of secondary or miscellaneous topics that have been less well covered. For example, methods for synthesizing and predicting the synthetic accessibility (SA) of designed compounds are important in practical drug development, and hardware/software resources for performing the computations in computer-aided drug design are crucial. Cloud computing and general purpose graphics processing unit (GPGPU) computing have been used in virtual screening and molecular dynamics simulations. Not surprisingly, there is a growing demand for computer systems which combine these resources. In the present review, we summarize and discuss these various topics of drug design.

Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics

PubMed Central

Fukunishi, Yoshifumi; Mashimo, Tadaaki; Misoo, Kiyotaka; Wakabayashi, Yoshinori; Miyaki, Toshiaki; Ohta, Seiji; Nakamura, Mayu; Ikeda, Kazuyoshi

2016-01-01

Abstract: Background Computer-aided drug design is still a state-of-the-art process in medicinal chemistry, and the main topics in this field have been extensively studied and well reviewed. These topics include compound databases, ligand-binding pocket prediction, protein-compound docking, virtual screening, target/off-target prediction, physical property prediction, molecular simulation and pharmacokinetics/pharmacodynamics (PK/PD) prediction. Message and Conclusion: However, there are also a number of secondary or miscellaneous topics that have been less well covered. For example, methods for synthesizing and predicting the synthetic accessibility (SA) of designed compounds are important in practical drug development, and hardware/software resources for performing the computations in computer-aided drug design are crucial. Cloud computing and general purpose graphics processing unit (GPGPU) computing have been used in virtual screening and molecular dynamics simulations. Not surprisingly, there is a growing demand for computer systems which combine these resources. In the present review, we summarize and discuss these various topics of drug design. PMID:27075578

High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva

PubMed Central

Cappato, Serena; Tonachini, Laura; Giacopelli, Francesca; Tirone, Mario; Galietta, Luis J. V.; Sormani, Martina; Giovenzana, Anna; Spinelli, Antonello E.; Canciani, Barbara; Brunelli, Silvia; Ravazzolo, Roberto

2016-01-01

ABSTRACT The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo. Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification. PMID:27125279

FDA 2011 process validation guidance: lifecycle compliance model.

PubMed

Campbell, Cliff

2014-01-01

This article has been written as a contribution to the industry's efforts in migrating from a document-driven to a data-driven compliance mindset. A combination of target product profile, control engineering, and general sum principle techniques is presented as the basis of a simple but scalable lifecycle compliance model in support of modernized process validation. Unit operations and significant variables occupy pole position within the model, documentation requirements being treated as a derivative or consequence of the modeling process. The quality system is repositioned as a subordinate of system quality, this being defined as the integral of related "system qualities". The article represents a structured interpretation of the U.S. Food and Drug Administration's 2011 Guidance for Industry on Process Validation and is based on the author's educational background and his manufacturing/consulting experience in the validation field. The U.S. Food and Drug Administration's Guidance for Industry on Process Validation (2011) provides a wide-ranging and rigorous outline of compliant drug manufacturing requirements relative to its 20(th) century predecessor (1987). Its declared focus is patient safety, and it identifies three inter-related (and obvious) stages of the compliance lifecycle. Firstly, processes must be designed, both from a technical and quality perspective. Secondly, processes must be qualified, providing evidence that the manufacturing facility is fully "roadworthy" and fit for its intended purpose. Thirdly, processes must be verified, meaning that commercial batches must be monitored to ensure that processes remain in a state of control throughout their lifetime.

Computer Aided Drug Design: Success and Limitations.

PubMed

Baig, Mohammad Hassan; Ahmad, Khurshid; Roy, Sudeep; Ashraf, Jalaluddin Mohammad; Adil, Mohd; Siddiqui, Mohammad Haris; Khan, Saif; Kamal, Mohammad Amjad; Provazník, Ivo; Choi, Inho

2016-01-01

Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

Surgical treatment of adolescent internal condylar resorption (AICR) with articular disc repositioning and orthognathic surgery in the growing patient--a pilot study.

PubMed

Bodine, Trevor P; Wolford, Larry M; Araujo, Eustaquio; Oliver, Donald R; Buschang, Peter H

2016-01-01

The aim of this study was to better understand how surgical repositioning and stabilization of anteriorly displaced articular discs using the Mitek mini-anchor technique affects condylar growth in growing patients with adolescent internal condylar resorption (AICR). Twenty-two adolescent patients diagnosed with AICR and anterior temporomandibular disc displacement were compared to untreated control subjects without AICR matched for age, sex, and Angle classification. Pre-surgical (T1 and T2) and post-surgical (T3 and T4) mandibular tracings were superimposed on natural stable structures to evaluate the horizontal, vertical, and total changes in the position of condylion. The treated group showed an overall decrease in condylar height pre-surgically and statistically significant changes in condylar growth direction between the pre- and post-surgical observation periods. Pre-surgically, the treated group showed significantly more posterior condylar growth than the control group; they also showed inferior condylar growth, while the controls showed superior growth. Controls and patients in the treated group showed no significant differences in condylar growth post-surgically. Adolescent patients diagnosed with AICR and anterior disc displacement treated with mandibular ramus and maxillary osteotomies, along with Mitek anchors to reposition internally deranged discs, showed post-surgical normalization of condylar growth.

Correlation between Trunk Posture and Neck Reposition Sense among Subjects with Forward Head Neck Postures

PubMed Central

Lee, Han Suk; Chung, Hyung Kuk; Park, Sun Wook

2015-01-01

Objective. To assess the correlation of abnormal trunk postures and reposition sense of subjects with forward head neck posture (FHP). Methods. In all, postures of 41 subjects were evaluated and the FHP and trunk posture including shoulder, scapular level, pelvic side, and anterior tilting degrees were analyzed. We used the head repositioning accuracy (HRA) test to evaluate neck position senses of neck flexion, neck extension, neck right and left side flexion, and neck right and left rotation and calculated the root mean square error in trials for each subject. Spearman's rank correlation coefficients and regression analysis were used to assess the degree of correlation between the trunk posture and HRA value, and a significance level of α = 0.05 was considered. Results. There were significant correlations between the HRA value of right side neck flexion and pelvic side tilt angle (p < 0.05). If pelvic side tilting angle increases by 1 degree, right side neck flexion increased by 0.76 degrees (p = 0.026). However, there were no significant correlations between other neck motions and trunk postures. Conclusion. Verifying pelvic postures should be prioritized when movement is limited due to the vitiation of the proprioceptive sense of neck caused by FHP. PMID:26583125

Biomechanical Evaluation of Different Fixation Methods for Mandibular Anterior Segmental Osteotomy Using Finite Element Analysis, Part Two: Superior Repositioning Surgery With Bone Allograft.

PubMed

Kilinç, Yeliz; Erkmen, Erkan; Kurt, Ahmet

2016-01-01

In this study, the biomechanical behavior of different fixation methods used to fix the mandibular anterior segment following various amounts of superior repositioning was evaluated by using Finite Element Analysis (FEA). The three-dimensional finite element models representing 3 and 5 mm superior repositioning were generated. The gap in between segments was assumed to be filled by block bone allograft and resignated to be in perfect contact with the mandible and segmented bone. Six different finite element models with 2 distinct mobilization rate including 3 different fixation configurations, double right L (DRL), double left L (DLL), or double I (DI) miniplates with monocortical screws, correspondingly were created. A comparative evaluation has been made under vertical, horizontal and oblique loads. The von Mises and principal maximum stress (Pmax) values were calculated by finite element solver programme. The first part of our ongoing Finite Element Analysis research has been addressed to the mechanical behavior of the same fixation configurations in nongrafted models. In comparison with the findings of the first part of the study, it was concluded that bone graft offers superior mechanical stability without any limitation of mobilization and less stress on the fixative appliances as well as in the bone.

Multicenter comparison of the efficacy on prevention of pressure ulcer in postoperative patients between two types of pressure-relieving mattresses in China

PubMed Central

Jiang, Qixia; Li, Xiaohua; Zhang, Aiqin; Guo, Yanxia; Liu, Yahong; Liu, Haiying; Qu, Xiaolong; Zhu, Yajun; Guo, Xiujun; Liu, Li; Zhang, Liyan; Bo, Suping; Jia, Jing; Chen, Yuejuan; Zhang, Rui; Wang, Jiandong

2014-01-01

Objective: Present study is designed to evaluate the effects of preventing pressure ulcer in surgical patients with two types of pressure-relieving mattresses. Methods: 1074 surgical patients from 12 hospitals in China were divided into A group (static air mattress with repositioning every 2 hours, n = 562) and B group (power pressure air mattress with repositioning every 2 hours, n = 512). The patient was subjected to a pressure-relieving mattress and observed from 0-5 days after surgery. Indications include the Braden scores, hospital-acquired pressure ulcers (HAPU) incidence and stage. Results: The Braden scores between two groups in five days after surgery were no significant (P > 0.05). The incidence of HAPU between two groups in same days also was no significant (1.07% vs. 0.98%, P > 0.05). The incidence of Stage I and stage II pressure ulcers in group A and B were 1.07% (6/562) and 0.98% (5/512), respectively (χ2 = 0.148, P = 0.882). Conclusion: The effects of preventing pressure ulcer in surgical patients with two types of pressure-relieving mattresses are similar, but the protocol by static air mattress with repositioning every 2 hours is benefit when no power. PMID:25356144

Cervical joint position sense in rugby players versus non-rugby players.

PubMed

Pinsault, Nicolas; Anxionnaz, Marion; Vuillerme, Nicolas

2010-05-01

To determine whether cervical joint position sense is modified by intensive rugby practice. A group-comparison study. University Medical Bioengineering Laboratory. Twenty young elite rugby players (10 forwards and 10 backs) and 10 young non-rugby elite sports players. Participants were asked to perform the cervicocephalic relocation test (CRT) to the neutral head position (NHP) that is, to reposition their head on their trunk, as accurately as possible, after full active left and right cervical rotation. Rugby players were asked to perform the CRT to NHP before and after a training session. Absolute and variable errors were used to assess accuracy and consistency of the repositioning for the three groups of Forwards, Backs and Non-rugby players, respectively. The 2 groups of Forwards and Backs exhibited higher absolute and variable errors than the group of Non-rugby players. No difference was found between the two groups of Forwards and Backs and no difference was found between Before and After the training session. The cervical joint position sense of young elite rugby players is altered compared to that of non-rugby players. Furthermore, Forwards and Backs demonstrated comparable repositioning errors before and after a specific training session, suggesting that cervical proprioceptive alteration is mainly due to tackling and not the scrum.

Nudging healthy food choices: a field experiment at the train station.

PubMed

Kroese, Floor M; Marchiori, David R; de Ridder, Denise T D

2016-06-01

Recognizing the mindless nature of many food decisions, it has been suggested that attempts to increase healthy eating should not focus on convincing people what is 'right' but rather aim to adjust the environment such that people are automatically directed toward healthy choices. This study investigated a nudge aiming to promote healthy food choices in train station snack shops. The nudge involved a repositioning of food products: healthy foods were placed at the cash register desk, while keeping unhealthy products available elsewhere in the shop. Three snack shops were included: a control condition; a nudge condition repositioning healthy products and a nudge + disclosure condition employing the same nudge together with an explanatory sign. Next to examining its effectiveness during 1 week, the study assessed customers' acceptance of the nudge. Controlling for a baseline week, more healthy (but not fewer unhealthy) products were sold in both nudge conditions, with no difference between the nudge and the nudge + disclosure condition. A majority of customers reported positive attitudes toward the nudge. Repositioning healthy foods is a simple, effective and well-accepted nudge to increase healthy purchases. Moreover, disclosing its purpose does not impact on effectiveness. © The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Computer-Assisted Drug Formulation Design: Novel Approach in Drug Delivery.

PubMed

Metwally, Abdelkader A; Hathout, Rania M

2015-08-03

We hypothesize that, by using several chemo/bio informatics tools and statistical computational methods, we can study and then predict the behavior of several drugs in model nanoparticulate lipid and polymeric systems. Accordingly, two different matrices comprising tripalmitin, a core component of solid lipid nanoparticles (SLN), and PLGA were first modeled using molecular dynamics simulation, and then the interaction of drugs with these systems was studied by means of computing the free energy of binding using the molecular docking technique. These binding energies were hence correlated with the loadings of these drugs in the nanoparticles obtained experimentally from the available literature. The obtained relations were verified experimentally in our laboratory using curcumin as a model drug. Artificial neural networks were then used to establish the effect of the drugs' molecular descriptors on the binding energies and hence on the drug loading. The results showed that the used soft computing methods can provide an accurate method for in silico prediction of drug loading in tripalmitin-based and PLGA nanoparticulate systems. These results have the prospective of being applied to other nano drug-carrier systems, and this integrated statistical and chemo/bio informatics approach offers a new toolbox to the formulation science by proposing what we present as computer-assisted drug formulation design (CADFD).

Biomechanical reposition techniques in anterior shoulder dislocation: a randomised multicentre clinical trial— the BRASD-trial protocol

PubMed Central

Roetman, Martijn H; Boeije, Tom; Roodheuvel, Floris; Mullaart-Jansen, Nieke; Peeters, Suzanne; Burg, Mike D

2017-01-01

Introduction Glenohumeral (shoulder) dislocations are the most common large joint dislocations seen in the emergency department (ED). They cause pain, often severe, and require timely interventions to minimise discomfort and tissue damage. Commonly used reposition or relocation techniques often involve traction and/or leverage. These techniques have high success rates but may be painful and time consuming. They may also cause complications. Recently, other techniques—the biomechanical reposition techniques (BRTs)—have become more popular since they may cause less pain, require less time and cause fewer complications. To our knowledge, no research exists comparing the various BRTs. Our objective is to establish which BRT or BRT combination is fastest, least painful and associated with the lowest complication rate for adult ED patients with anterior glenohumeral dislocations (AGDs). Methods and analysis Adults presenting to the participating EDs with isolated AGDs, as determined by radiographs, will be randomised to one of three BRTs: Cunningham, modified Milch or scapular manipulation. Main study parameters/endpoints are ED length of stay and patients’ self-report of pain. Secondary study parameters/endpoints are procedure times, need for analgesic and/or sedative medications, iatrogenic complications and rates of successful reduction. Ethics and dissemination Non-biomechanical AGD repositioning techniques based on traction and/or leverage are inherently painful and potentially harmful. We believe that the three BRTs used in this study are more physiological, more patient friendly, less likely to cause pain, more time efficient and less likely to produce complications. By comparing these three techniques, we hope to improve the care provided to adults with acute AGDs by reducing their ED length of stay and minimising pain and procedure-related complications. We also hope to define which of the three BRTs is quickest, most likely to be successful and least likely to require sedative or analgesic medications to achieve reduction. Trial registration number NTR5839. PMID:28729305

Cervicocephalic kinesthetic sensibility and postural balance in patients with nontraumatic chronic neck pain – a pilot study

PubMed Central

Palmgren, Per J; Andreasson, Daniel; Eriksson, Magnus; Hägglund, Andreas

2009-01-01

Background Although cervical pain is widespread, most victims are only mildly and occasionally affected. A minority, however, suffer chronic pain and/or functional impairments. Although there is abundant literature regarding nontraumatic neck pain, little focuses on diagnostic criteria. During the last decade, research on neck pain has been designed to evaluate underlying pathophysiological mechanisms, without noteworthy success. Independent researchers have investigated postural balance and cervicocephalic kinesthetic sensibility among patients with chronic neck pain, and have (in most cases) concluded the source of the problem is a reduced ability in the neck's proprioceptive system. Here, we investigated cervicocephalic kinesthetic sensibility and postural balance among patients with nontraumatic chronic neck pain. Methods Ours was a two-group, observational pilot study of patients with complaints of continuous neck pain during the 3 months prior to recruitment. Thirteen patients with chronic neck pain of nontraumatic origin were recruited from an institutional outpatient clinic. Sixteen healthy persons were recruited as a control group. Cervicocephalic kinesthetic sensibility was assessed by exploring head repositioning accuracy and postural balance was measured with computerized static posturography. Results Parameters of cervicocephalic kinesthetic sensibility were not reduced. However, in one of six test movements (flexion), global repositioning errors were significantly larger in the experimental group than in the control group (p < .05). Measurements did not demonstrate any general impaired postural balance, and varied substantially among participants in both groups. Conclusion In patients with nontraumatic chronic neck pain, we found statistically significant global repositioning errors in only one of six test movements. In this cohort, we found no evidence of impaired postural balance. Head repositioning accuracy and computerized static posturography are imperfect measures of functional proprioceptive impairments. Validity of (and procedures for using) these instruments demand further investigation. Trial registration Current Controlled Trials ISRCTN96873990 PMID:19566929

Chlamydia Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning.

PubMed

Wesolowski, Jordan; Weber, Mary M; Nawrotek, Agata; Dooley, Cheryl A; Calderon, Mike; St Croix, Claudette M; Hackstadt, Ted; Cherfils, Jacqueline; Paumet, Fabienne

2017-05-02

The intracellular bacterium Chlamydia trachomatis develops in a parasitic compartment called the inclusion. Posttranslationally modified microtubules encase the inclusion, controlling the positioning of Golgi complex fragments around the inclusion. The molecular mechanisms by which Chlamydia coopts the host cytoskeleton and the Golgi complex to sustain its infectious compartment are unknown. Here, using a genetically modified Chlamydia strain, we discovered that both posttranslationally modified microtubules and Golgi complex positioning around the inclusion are controlled by the chlamydial inclusion protein CT813/CTL0184/InaC and host ARF GTPases. CT813 recruits ARF1 and ARF4 to the inclusion membrane, where they induce posttranslationally modified microtubules. Similarly, both ARF isoforms are required for the repositioning of Golgi complex fragments around the inclusion. We demonstrate that CT813 directly recruits ARF GTPases on the inclusion membrane and plays a pivotal role in their activation. Together, these results reveal that Chlamydia uses CT813 to hijack ARF GTPases to couple posttranslationally modified microtubules and Golgi complex repositioning at the inclusion. IMPORTANCE Chlamydia trachomatis is an important cause of morbidity and a significant economic burden in the world. However, how Chlamydia develops its intracellular compartment, the so-called inclusion, is poorly understood. Using genetically engineered Chlamydia mutants, we discovered that the effector protein CT813 recruits and activates host ADP-ribosylation factor 1 (ARF1) and ARF4 to regulate microtubules. In this context, CT813 acts as a molecular platform that induces the posttranslational modification of microtubules around the inclusion. These cages are then used to reposition the Golgi complex during infection and promote the development of the inclusion. This study provides the first evidence that ARF1 and ARF4 play critical roles in controlling posttranslationally modified microtubules around the inclusion and that Chlamydia trachomatis hijacks this novel function of ARF to reposition the Golgi complex. Copyright © 2017 Wesolowski et al.

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells

PubMed Central

Aguirre-Alvarado, Charmina; Segura-Cabrera, Aldo; Velázquez-Quesada, Inés; Hernández-Esquivel, Miguel A.; García-Pérez, Carlos A.; Guerrero-Rodríguez, Sandra L.; Ruiz, Angel J.; Rodríguez-Moreno, Andrea; Pérez-Tapia, Sonia M.; Velasco-Velázquez, Marco A.

2016-01-01

CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24− cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists. PMID:27009862

DiseaseConnect: a comprehensive web server for mechanism-based disease–disease connections

PubMed Central

Liu, Chun-Chi; Tseng, Yu-Ting; Li, Wenyuan; Wu, Chia-Yu; Mayzus, Ilya; Rzhetsky, Andrey; Sun, Fengzhu; Waterman, Michael; Chen, Jeremy J. W.; Chaudhary, Preet M.; Loscalzo, Joseph; Crandall, Edward; Zhou, Xianghong Jasmine

2014-01-01

The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConnect, the first public web server, integrates comprehensive omics and literature data, including a large amount of gene expression data, Genome-Wide Association Studies catalog, and text-mined knowledge, to discover disease–disease connectivity via common molecular mechanisms. Moreover, the clinical comorbidity data and a comprehensive compilation of known drug–disease relationships are additionally utilized for advancing the understanding of the disease landscape and for facilitating the mechanism-based development of new drug treatments. PMID:24895436

A systems pharmacology-oriented discovery of a new therapeutic use of the TCM formula Liuweiwuling for liver failure.

PubMed

Wang, Jia-Bo; Cui, He-Rong; Wang, Rui-Lin; Zhang, Cong-En; Niu, Ming; Bai, Zhao-Fang; Xu, Gen-Hua; Li, Peng-Yan; Jiang, Wen-Yan; Han, Jing-Jing; Ma, Xiao; Cai, Guang-Ming; Li, Rui-Sheng; Zhang, Li-Ping; Xiao, Xiao-He

2018-04-04

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells.

PubMed

Aguirre-Alvarado, Charmina; Segura-Cabrera, Aldo; Velázquez-Quesada, Inés; Hernández-Esquivel, Miguel A; García-Pérez, Carlos A; Guerrero-Rodríguez, Sandra L; Ruiz-Moreno, Angel J; Rodríguez-Moreno, Andrea; Pérez-Tapia, Sonia M; Velasco-Velázquez, Marco A

2016-04-26

CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24- cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists.

COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

PubMed Central

Kapetanovic, I.M.

2008-01-01

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

Drug knowledge expressed as computable semantic triples.

PubMed

Elkin, Peter L; Carter, John S; Nabar, Manasi; Tuttle, Mark; Lincoln, Michael; Brown, Steven H

2011-01-01

The majority of questions that arise in the practice of medicine relate to drug information. Additionally, adverse reactions account for as many as 98,000 deaths per year in the United States. Adverse drug reactions account for a significant portion of those errors. Many authors believe that clinical decision support associated with computerized physician order entry has the potential to decrease this adverse drug event rate. This decision support requires knowledge to drive the process. One important and rich source of drug knowledge is the DailyMed product labels. In this project we used computationally extracted SNOMED CT™ codified data associated with each section of each product label as input to a rules engine that created computable assertional knowledge in the form of semantic triples. These are expressed in the form of "Drug" HasIndication "SNOMED CT™". The information density of drug labels is deep, broad and quite substantial. By providing a computable form of this information content from drug labels we make these important axioms (facts) more accessible to computer programs designed to support improved care.

Computational Fragment-Based Drug Design: Current Trends, Strategies, and Applications.

PubMed

Bian, Yuemin; Xie, Xiang-Qun Sean

2018-04-09

Fragment-based drug design (FBDD) has become an effective methodology for drug development for decades. Successful applications of this strategy brought both opportunities and challenges to the field of Pharmaceutical Science. Recent progress in the computational fragment-based drug design provide an additional approach for future research in a time- and labor-efficient manner. Combining multiple in silico methodologies, computational FBDD possesses flexibilities on fragment library selection, protein model generation, and fragments/compounds docking mode prediction. These characteristics provide computational FBDD superiority in designing novel and potential compounds for a certain target. The purpose of this review is to discuss the latest advances, ranging from commonly used strategies to novel concepts and technologies in computational fragment-based drug design. Particularly, in this review, specifications and advantages are compared between experimental and computational FBDD, and additionally, limitations and future prospective are discussed and emphasized.

Locus-specific gene repositioning in prostate cancer

PubMed Central

Leshner, Marc; Devine, Michelle; Roloff, Gregory W.; True, Lawrence D.; Misteli, Tom; Meaburn, Karen J.

2016-01-01

Genes occupy preferred spatial positions within interphase cell nuclei. However, positioning patterns are not an innate feature of a locus, and genes can alter their localization in response to physiological and pathological changes. Here we screen the radial positioning patterns of 40 genes in normal, hyperplasic, and malignant human prostate tissues. We find that the overall spatial organization of the genome in prostate tissue is largely conserved among individuals. We identify three genes whose nuclear positions are robustly altered in neoplastic prostate tissues. FLI1 and MMP9 position differently in prostate cancer than in normal tissue and prostate hyperplasia, whereas MMP2 is repositioned in both prostate cancer and hyperplasia. Our data point to locus-specific reorganization of the genome during prostate disease. PMID:26564800

The effects of transcutaneous electrical nerve stimulation on joint position sense in patients with knee joint osteoarthritis.

PubMed

Shirazi, Zahra Rojhani; Shafaee, Razieh; Abbasi, Leila

2014-10-01

To study the effects of transcutaneous electrical nerve stimulation (TENS) on joint position sense (JPS) in knee osteoarthritis (OA) subjects. Thirty subjects with knee OA (40-60 years old) using non-random sampling participated in this study. In order to evaluate the absolute error of repositioning of the knee joint, Qualysis Track Manager system was used and sensory electrical stimulation was applied through the TENS device. The mean errors in repositioning of the joint, in two position of the knee joint with 20 and 60 degree angle, after applying the TENS was significantly decreased (p < 0.05). Application of TENS in subjects with knee OA could improve JPS in these subjects.

The effect of balance training on cervical sensorimotor function and neck pain.

PubMed

Beinert, Konstantin; Taube, Wolfgang

2013-01-01

The authors' aim was to evaluate the effect of balance training on cervical joint position sense in people with subclinical neck pain. Thirty-four participants were randomly assigned to balance training or to stay active. Sensorimotor function was determined before and after 5 weeks of training by assessing the ability to reproduce the neutral head position and a predefined rotated head position. After balance training, the intervention group showed improved joint repositioning accuracy and decreased pain whereas no effects were observed in the control group. A weak correlation was identified between reduced neck pain intensity and improved joint repositioning. The present data demonstrate that balance training can effectively improve cervical sensorimotor function and decrease neck pain intensity.

Multidisciplinary approach in the management of a complicated crown root fracture.

PubMed

Shin, J H; Kim, J E; Kim, R J

2013-06-01

This article describes the management of a complicated crown root fracture. A young patient presented with a crown root fracture of the maxillary left central incisor with an oblique subgingival fracture line. A multidisciplinary treatment approach including endodontic treatment, orthodontic extrusion, surgical extraction and intra-alveolar repositioning was used to gain sufficient crown length of the fractured maxillary incisor. The coronally repositioned maxillary left central incisor was stabilised by sutures and a resin wire splint. A resin core was built up followed by fabrication of an all-ceramic crown. Clinical and radiographic follow-up of the maxillary left central incisor after 24 months showed no signs of bone resorption or pathology and good aesthetics and functions were maintained.

A laboratory investigation of the accuracy of the repositioning impression coping technique at the implant level for single-tooth implants.

PubMed

Daoudi, M Firas; Setchell, Derrick J; Searson, Lloyd J

2003-03-01

This study investigated the accuracy of the repositioning impression technique at the implant level using vinyl polysiloxane impression material. Three groups each of ten senior dentists, postgraduate students and technicians were asked to use this technique to record the position of an implant in a master model. The Reflex Microscope was used to measure variations between the resulting casts and the master model. Significant difference between the casts and the master model in the X and Y-axes (p < 0.01) was recorded. Alarming inclinational and rotational errors for the implant analogue position were measured with all groups of operators. Similar distortion in the Z-axis was recorded.

Discovery of new erbB4 inhibitors: Repositioning an orphan chemical library by inverse virtual screening.

PubMed

Giordano, Assunta; Forte, Giovanni; Massimo, Luigia; Riccio, Raffaele; Bifulco, Giuseppe; Di Micco, Simone

2018-04-12

Inverse Virtual Screening (IVS) is a docking based approach aimed to the evaluation of the virtual ability of a single compound to interact with a library of proteins. For the first time, we applied this methodology to a library of synthetic compounds, which proved to be inactive towards the target they were initially designed for. Trifluoromethyl-benzenesulfonamides 3-21 were repositioned by means of IVS identifying new lead compounds (14-16, 19 and 20) for the inhibition of erbB4 in the low micromolar range. Among these, compound 20 exhibited an interesting value of IC 50 on MCF7 cell lines, thus validating IVS in lead repurposing. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

What is behind "centromere repositioning"?

PubMed

Schubert, Ingo

2018-06-01

An increasing number of observations suggest an evolutionary switch of centromere position on monocentric eukaryotic chromosomes which otherwise display a conserved sequence of genes and markers. Such observations are particularly frequent for primates and equidae (for review see Heredity 108:59-67, 2012) but occur also in marsupials (J Hered 96:217-224, 2005) and in plants (Chromosome Res 25:299-311, 2017 and references therein). The actual mechanism(s) behind remained unclear in many cases (Proc Natl Acad Sci USA 101:6542-6547, 2004; Trends Genet 30:66-74, 2014). The same is true for de novo centromere formation on chromosomes lacking an active centromere. This article focuses on recent reports on centromere repositioning and possible mechanisms behind and addresses open questions.

Benign paroxysmal positional vertigo secondary to laparoscopic surgery

PubMed Central

Shan, Xizheng; Wang, Amy; Wang, Entong

2017-01-01

Objectives: Benign paroxysmal positional vertigo is a common vestibular disorder and it may be idiopathic or secondary to some conditions such as surgery, but rare following laparoscopic surgery. Methods: We report two cases of benign paroxysmal positional vertigo secondary to laparoscopic surgery, one after laparoscopic cholecystectomy in a 51-year-old man and another following laparoscopic hysterectomy in a 60-year-old woman. Results: Both patients were treated successfully with manual or device-assisted canalith repositioning maneuvers, with no recurrence on the follow-up of 6 -18 months. Conclusions: Benign paroxysmal positional vertigo is a rare but possible complication of laparoscopic surgery. Both manual and device-assisted repositioning maneuvers are effective treatments for this condition, with good efficacy and prognosis. PMID:28255446

[Fractures of the proximal interphalangeal joint: Diagnostic and operative therapy options].

PubMed

Unglaub, F; Langer, M F; Hahn, P; Müller, L P; Ahrens, C; Spies, C K

2016-02-01

Joint fractures of the fingers often entail operative interventions in contrast to extra-articular fractures. These types of fracture are inclined to dislocate in addition to the actual fracture. The proximal interphalangeal (PIP) joint in particular often shows comminuted fractures due to the long leverage of the finger and a relatively small diameter of the joint. The clinical examination, X-ray diagnostics and if necessary computed tomography allow the classification into stable and unstable fractures. Unstable fractures must be treated by surgical reduction and fixation. A multitude of operative techniques are available for these mostly complicated fractures. The foremost goal is a stable osteosynthesis of the fracture with repositioning of the dislocation, which enables early physiotherapy in order to prevent tendon adhesion and contracture. This article presents the different types of PIP joint fractures, their specific surgical treatment and postoperative treatment regimens.

Computer-aided design and manufacturing of surgical templates and their clinical applications: a review.

PubMed

Chen, Xiaojun; Xu, Lu; Wang, Wei; Li, Xing; Sun, Yi; Politis, Constantinus

2016-09-01

The surgical template is a guide aimed at directing the implant placement, tumor resection, osteotomy and bone repositioning. Using it, preoperative planning can be transferred to the actual surgical site, and the precision, safety and reliability of the surgery can be improved. However, the actual workflow of the surgical template design and manufacturing is quite complicated before the final clinical application. The major goal of the paper is to provide a comprehensive reference source of the current and future development of the template design and manufacturing for relevant researchers. Expert commentary: This paper aims to present a review of the necessary procedures in the template-guided surgery including the image processing, 3D visualization, preoperative planning, surgical guide design and manufacturing. In addition, the template-guided clinical applications for various kinds of surgeries are reviewed, and it demonstrated that the precision of the surgery has been improved compared with the non-guided operations.

Reducing the number of templates for aligned-spin compact binary coalescence gravitational wave searches using metric-agnostic template nudging

NASA Astrophysics Data System (ADS)

Indik, Nathaniel; Fehrmann, Henning; Harke, Franz; Krishnan, Badri; Nielsen, Alex B.

2018-06-01

Efficient multidimensional template placement is crucial in computationally intensive matched-filtering searches for gravitational waves (GWs). Here, we implement the neighboring cell algorithm (NCA) to improve the detection volume of an existing compact binary coalescence (CBC) template bank. This algorithm has already been successfully applied for a binary millisecond pulsar search in data from the Fermi satellite. It repositions templates from overdense regions to underdense regions and reduces the number of templates that would have been required by a stochastic method to achieve the same detection volume. Our method is readily generalizable to other CBC parameter spaces. Here we apply this method to the aligned-single-spin neutron star-black hole binary coalescence inspiral-merger-ringdown gravitational wave parameter space. We show that the template nudging algorithm can attain the equivalent effectualness of the stochastic method with 12% fewer templates.

21 CFR 810.3 - Computation of time.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Computation of time. 810.3 Section 810.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... of time begins to run shall not be included. The computation of time is based only on working days. ...

21 CFR 810.3 - Computation of time.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Computation of time. 810.3 Section 810.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... of time begins to run shall not be included. The computation of time is based only on working days. ...

[Computational chemistry in structure-based drug design].

PubMed

Cao, Ran; Li, Wei; Sun, Han-Zi; Zhou, Yu; Huang, Niu

2013-07-01

Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.

Integration of drug dosing data with physiological data streams using a cloud computing paradigm.

PubMed

Bressan, Nadja; James, Andrew; McGregor, Carolyn

2013-01-01

Many drugs are used during the provision of intensive care for the preterm newborn infant. Recommendations for drug dosing in newborns depend upon data from population based pharmacokinetic research. There is a need to be able to modify drug dosing in response to the preterm infant's response to the standard dosing recommendations. The real-time integration of physiological data with drug dosing data would facilitate individualised drug dosing for these immature infants. This paper proposes the use of a novel computational framework that employs real-time, temporal data analysis for this task. Deployment of the framework within the cloud computing paradigm will enable widespread distribution of individualized drug dosing for newborn infants.

21 CFR 20.117 - New drug information.

Code of Federal Regulations, 2011 CFR

2011-04-01

... covered by such applications. (b) Other computer printouts containing IND and NDA information are... computer printouts are available for public inspection in the Food and Drug Administration's Freedom of Information Public Room: (1) A numerical listing of all new drug applications and abbreviated new drug...

Whole-body computed tomography in trauma patients: optimization of the patient scanning position significantly shortens examination time while maintaining diagnostic image quality.

PubMed

Hickethier, Tilman; Mammadov, Kamal; Baeßler, Bettina; Lichtenstein, Thorsten; Hinkelbein, Jochen; Smith, Lucy; Plum, Patrick Sven; Chon, Seung-Hun; Maintz, David; Chang, De-Hua

2018-01-01

The study was conducted to compare examination time and artifact vulnerability of whole-body computed tomographies (wbCTs) for trauma patients using conventional or optimized patient positioning. Examination time was measured in 100 patients scanned with conventional protocol (Group A: arms positioned alongside the body for head and neck imaging and over the head for trunk imaging) and 100 patients scanned with optimized protocol (Group B: arms flexed on a chest pillow without repositioning). Additionally, influence of two different scanning protocols on image quality in the most relevant body regions was assessed by two blinded readers. Total wbCT duration was about 35% or 3:46 min shorter in B than in A. Artifacts in aorta (27 vs 6%), liver (40 vs 8%) and spleen (27 vs 5%) occurred significantly more often in B than in A. No incident of non-diagnostic image quality was reported, and no significant differences for lungs and spine were found. An optimized wbCT positioning protocol for trauma patients allows a significant reduction of examination time while still maintaining diagnostic image quality.

Computational methods in drug discovery

PubMed Central

Leelananda, Sumudu P

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. PMID:28144341

Computational methods in drug discovery.

PubMed

Leelananda, Sumudu P; Lindert, Steffen

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein-ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

Repositioning the substrate activity screening (SAS) approach as a fragment-based method for identification of weak binders.

PubMed

Gladysz, Rafaela; Cleenewerck, Matthias; Joossens, Jurgen; Lambeir, Anne-Marie; Augustyns, Koen; Van der Veken, Pieter

2014-10-13

Fragment-based drug discovery (FBDD) has evolved into an established approach for "hit" identification. Typically, most applications of FBDD depend on specialised cost- and time-intensive biophysical techniques. The substrate activity screening (SAS) approach has been proposed as a relatively cheap and straightforward alternative for identification of fragments for enzyme inhibitors. We have investigated SAS for the discovery of inhibitors of oncology target urokinase (uPA). Although our results support the key hypotheses of SAS, we also encountered a number of unreported limitations. In response, we propose an efficient modified methodology: "MSAS" (modified substrate activity screening). MSAS circumvents the limitations of SAS and broadens its scope by providing additional fragments and more coherent SAR data. As well as presenting and validating MSAS, this study expands existing SAR knowledge for the S1 pocket of uPA and reports new reversible and irreversible uPA inhibitor scaffolds. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Artemisinins, new miconazole potentiators resulting in increased activity against Candida albicans biofilms.

PubMed

De Cremer, Kaat; Lanckacker, Ellen; Cools, Tanne L; Bax, Marijke; De Brucker, Katrijn; Cos, Paul; Cammue, Bruno P A; Thevissen, Karin

2015-01-01

Mucosal biofilm-related fungal infections are very common, and the incidence of recurrent oral and vulvovaginal candidiasis is significant. As resistance to azoles (the preferred treatment) is occurring, we aimed at identifying compounds that increase the activity of miconazole against Candida albicans biofilms. We screened 1,600 compounds of a drug-repositioning library in combination with a subinhibitory concentration of miconazole. Synergy between the best identified potentiators and miconazole was characterized by checkerboard analyses and fractional inhibitory concentration indices. Hexachlorophene, pyrvinium pamoate, and artesunate act synergistically with miconazole in affecting C. albicans biofilms. Synergy was most pronounced for artesunate and structural homologues thereof. No synergistic effect could be observed between artesunate and fluconazole, caspofungin, or amphotericin B. Our data reveal enhancement of the antibiofilm activity of miconazole by artesunate, pointing to potential combination therapy consisting of miconazole and artesunate to treat C. albicans biofilm-related infections. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Overcoming mutation-based resistance to antiandrogens with rational drug design

PubMed Central

Balbas, Minna D; Evans, Michael J; Hosfield, David J; Wongvipat, John; Arora, Vivek K; Watson, Philip A; Chen, Yu; Greene, Geoffrey L; Shen, Yang; Sawyers, Charles L

2013-01-01

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide. DOI: http://dx.doi.org/10.7554/eLife.00499.001 PMID:23580326