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https://www.readbyqxmd.com/read/29891731/local-bdnf-delivery-to-the-injured-cervical-spinal-cord-using-an-engineered-hydrogel-enhances-diaphragmatic-respiratory-function
#1
Biswarup Ghosh, Zhicheng Wang, Jia Nong, Mark W Urban, Zhiling Zhang, Victoria A Trovillion, Megan C Wright, Yinghui Zhong, Angelo C Lepore
We developed an innovative biomaterial-based approach to repair the critical neural circuitry that controls diaphragm activation by locally delivering brain-derived neurotrophic factor (BDNF) to injured cervical spinal cord. BDNF can be used to restore respiratory function via a number of potential repair mechanisms; however, widespread BDNF biodistribution resulting from delivery methods such as systemic injection or lumbar puncture can lead to inefficient drug delivery and adverse side effects. As a viable alternative, we developed a novel hydrogel-based system loaded with polysaccharide-BDNF particles self-assembled by electrostatic interactions that can be safely implanted in the intrathecal space for achieving local BDNF delivery with controlled dosing and duration...
June 11, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29773677/the-relative-resistance-of-children-to-sepsis-mortality-from-pathways-to-drug-candidates
#2
Rose B Joachim, Gabriel M Altschuler, John N Hutchinson, Hector R Wong, Winston A Hide, Lester Kobzik
Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays...
May 17, 2018: Molecular Systems Biology
https://www.readbyqxmd.com/read/29767372/bayesian-network-to-infer-drug-induced-apoptosis-circuits-from-connectivity-map-data
#3
Jiyang Yu, Jose M Silva
The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. As most targeted anticancer therapeutics aim to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using Connectivity MAP microarray-based gene expression data, we applied a Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular pathway...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29650251/exploring-the-molecular-mechanisms-of-traditional-chinese-medicine-components-using-gene-expression-signatures-and-connectivity-map
#4
Minjae Yoo, Jimin Shin, Hyunmin Kim, Jihye Kim, Jaewoo Kang, Aik Choon Tan
BACKGROUND AND OBJECTIVE: Traditional Chinese Medicine (TCM) has been practiced over thousands of years in China and other Asian countries for treating various symptoms and diseases. However, the underlying molecular mechanisms of TCM are poorly understood, partly due to the "multi-component, multi-target" nature of TCM. To uncover the molecular mechanisms of TCM, we perform comprehensive gene expression analysis using connectivity map. METHODS: We interrogated gene expression signatures obtained 102 TCM components using the next generation Connectivity Map (CMap) resource...
April 4, 2018: Computer Methods and Programs in Biomedicine
https://www.readbyqxmd.com/read/29605259/gene-expression-profiling-coupled-with-connectivity-map-database-mining-reveals-potential-therapeutic-drugs-for-hirschsprung-disease
#5
Shang-Jie Xiao, Xiao-Chun Zhu, Hua Deng, Wei-Ping Zhou, Wen-Yi Yang, Li-Ke Yuan, Jiang-Yu Zhang, Song Tian, Lu Xu, Liang Zhang, Hui-Min Xia
BACKGROUND: Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD...
March 4, 2018: Journal of Pediatric Surgery
https://www.readbyqxmd.com/read/29588458/personalised-drug-repositioning-for-clear-cell-renal-cell-carcinoma-using-gene-expression
#6
Karel K M Koudijs, Anton G T Terwisscha van Scheltinga, Stefan Böhringer, Kirsten J M Schimmel, Henk-Jan Guchelaar
Reversal of cancer gene expression is predictive of therapeutic potential and can be used to find new indications for existing drugs (drug repositioning). Gene expression reversal potential is currently calculated, in almost all studies, by pre-aggregating all tumour samples into a single group signature or a limited number of molecular subtype signatures. Here, we investigate whether drug repositioning based on individual tumour sample gene expression signatures outperforms the use of tumour group and subtype signatures...
March 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29558515/new-drug-candidates-for-treatment-of-atypical-meningiomas-an-integrated-approach-using-gene-expression-signatures-for-drug-repurposing
#7
Zsolt Zador, Andrew T King, Nophar Geifman
BACKGROUND: Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision and radiotherapy remains the mainstay therapy but medical treatments are limited. We explore new drug candidates using computational drug repurposing based on the gene expression signature of atypical meningioma tissue with subsequent analysis of drug-generated expression profiles. We further explore possible mechanisms of action for the identified drug candidates using ingenuity pathway analysis (IPA)...
2018: PloS One
https://www.readbyqxmd.com/read/29195078/a-next-generation-connectivity-map-l1000-platform-and-the-first-1-000-000-profiles
#8
Aravind Subramanian, Rajiv Narayan, Steven M Corsello, David D Peck, Ted E Natoli, Xiaodong Lu, Joshua Gould, John F Davis, Andrew A Tubelli, Jacob K Asiedu, David L Lahr, Jodi E Hirschman, Zihan Liu, Melanie Donahue, Bina Julian, Mariya Khan, David Wadden, Ian C Smith, Daniel Lam, Arthur Liberzon, Courtney Toder, Mukta Bagul, Marek Orzechowski, Oana M Enache, Federica Piccioni, Sarah A Johnson, Nicholas J Lyons, Alice H Berger, Alykhan F Shamji, Angela N Brooks, Anita Vrcic, Corey Flynn, Jacqueline Rosains, David Y Takeda, Roger Hu, Desiree Davison, Justin Lamb, Kristin Ardlie, Larson Hogstrom, Peyton Greenside, Nathanael S Gray, Paul A Clemons, Serena Silver, Xiaoyun Wu, Wen-Ning Zhao, Willis Read-Button, Xiaohua Wu, Stephen J Haggarty, Lucienne V Ronco, Jesse S Boehm, Stuart L Schreiber, John G Doench, Joshua A Bittker, David E Root, Bang Wong, Todd R Golub
We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29156785/-in-silico-and-in-vitro-identification-of-inhibitory-activities-of-sorafenib-on-histone-deacetylases-in-hepatocellular-carcinoma-cells
#9
Tsang-Pai Liu, Yi-Han Hong, Pei-Ming Yang
Although sorafenib has been approved for treating hepatocellular carcinoma (HCC), clinical results are not satisfactory. Polypharmacology (one drug with multiple molecular targets) is viewed as an attractive strategy for identifying novel mechanisms of a drug and then rationally designing more-effective next-generation therapeutic agents. In this study, a polypharmacological study of sorafenib was performed by mining the next-generation Connectivity Map (CMap) database, CLUE (https://clue.io/). We found that sorafenib may act as a histone deacetylase (HDAC) inhibitor based on similar gene expression profiles...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29149772/natural-history-of-infantile-onset-spinal-muscular-atrophy
#10
MULTICENTER STUDY
Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Susan T Iannaccone, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months...
December 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29081411/identification-of-breast-cancer-hub-genes-and-analysis-of-prognostic-values-using-integrated-bioinformatics-analysis
#11
Enhao Fang, Xiuqing Zhang
BACKGROUND: Breast cancer (BC) is the second most common cause of death from cancer in women in the United States. As the molecular mechanism of BC has not yet been completely discovered, identification of hub genes and pathways of this disease is of importance for revealing molecular mechanism of breast cancer initiation and progression. OBJECTIVE: This study aimed to identify potential biomarkers and survival analysis of hub genes for BC treatment. METHODS: The differentially expressed genes (DEGs) between breast cancer and normal cells were screened using microarray data obtained from the Gene Expression Omnibus (GEO) database...
December 12, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28962576/statistically-controlled-identification-of-differentially-expressed-genes-in-one-to-one-cell-line-comparisons-of-the-cmap-database-for-drug-repositioning
#12
Jun He, Haidan Yan, Hao Cai, Xiangyu Li, Qingzhou Guan, Weicheng Zheng, Rou Chen, Huaping Liu, Kai Song, Zheng Guo, Xianlong Wang
BACKGROUND: The Connectivity Map (CMAP) database, an important public data source for drug repositioning, archives gene expression profiles from cancer cell lines treated with and without bioactive small molecules. However, there are only one or two technical replicates for each cell line under one treatment condition. For such small-scale data, current fold-changes-based methods lack statistical control in identifying differentially expressed genes (DEGs) in treated cells. Especially, one-to-one comparison may result in too many drug-irrelevant DEGs due to random experimental factors...
September 29, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28930822/five-years-experience-on-3-4-diaminopyridine-phosphate-in-lambert-eaton-syndrome-case-reports
#13
Simona Portaro, Teresa Brizzi, Stefano Sinicropi, Alberto Cacciola, Maria Cristina De Cola, Alessia Bramanti, Demetrio Milardi, Antonino Lupica, Placido Bramanti, Antonio Toscano, Carmelo Rodolico
RATIONALE: To report our experience on 7 patients (4 males and 3 females), affected by nonparaneoplastic Lambert-Eaton myasthenic syndrome, treated with 3,4-diaminopyridine phosphate (3,4-DAPP) either alone or in combination with other immunosuppressants or steroids. PATIENT CONCERNS: Patients have been evaluated at specific timepoints (ie, baseline and last 5 year follow-up), with neurological examination, autoantibodies against presynaptic voltage-gated Cav2.1 (P/Q type) calcium ion channel (VGCC) dosage, neurophysiological evaluation focusing on the increased amplitude of the compound muscle action potential (cMAP) after maximum voluntary effort, quantitative myasthenia gravis (QMG) and activities of daily living scales, and autonomic nervous system involvement evaluation...
September 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28615526/identifying-prognostic-signature-in-ovarian-cancer-using-dirgenerank
#14
Jian-Yong Wang, Ling-Ling Chen, Xiong-Hui Zhou
Identifying the prognostic genes in cancer is essential not only for the treatment of cancer patients, but also for drug discovery. However, it's still a big challenge to select the prognostic genes that can distinguish the risk of cancer patients across various data sets because of tumor heterogeneity. In this situation, the selected genes whose expression levels are statistically related to prognostic risks may be passengers. In this paper, based on gene expression data and prognostic data of ovarian cancer patients, we used conditional mutual information to construct gene dependency network in which the nodes (genes) with more out-degrees have more chances to be the modulators of cancer prognosis...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28599476/identification-of-gene-markers-associated-with-metastasis-in-clear-cell-renal-cell-carcinoma
#15
Hailing Yang, Pengfei Huo, Guozhang Hu, Bo Wei, Dalian Kong, Hongjun Li
The present study aimed to screen potential target genes for the early diagnosis and treatment of early metastatic clear cell renal cell carcinoma (ccRCC) using the microarray data of early metastatic and non-metastatic ccRCC samples. The DNA microarray dataset GSE47352 was downloaded from Gene Expression Omnibus and included 4 early metastatic and 5 non-metastatic ccRCC samples. Differentially expressed genes (DEGs) were screened using the limma package. Then, pheatmap package was used to conduct two-way clustering for the DEGs...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28587109/identification-of-non-electrophilic-nrf2-activators-from-approved-drugs
#16
Qing-Ye Zhang, Xin-Yi Chu, Ling-Han Jiang, Meng-Yuan Liu, Zhi-Ling Mei, Hong-Yu Zhang
Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of 'off-target' effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic...
May 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28472897/the-anticancer-effect-of-mebendazole-may-be-due-to-m1-monocyte-macrophage-activation-via-erk1-2-and-tlr8-dependent-inflammasome-activation
#17
Kristin Blom, Wojciech Senkowski, Malin Jarvius, Malin Berglund, Jenny Rubin, Lena Lenhammar, Vendela Parrow, Claes Andersson, Angelica Loskog, Mårten Fryknäs, Peter Nygren, Rolf Larsson
Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation...
August 2017: Immunopharmacology and Immunotoxicology
https://www.readbyqxmd.com/read/28256512/transcriptome-based-repurposing-of-apigenin-as-a-potential-anti-fibrotic-agent-targeting-hepatic-stellate-cells
#18
Daniel F Hicks, Nicolas Goossens, Ana Blas-García, Takuma Tsuchida, Benjamin Wooden, Michael C Wallace, Natalia Nieto, Abigale Lade, Benjamin Redhead, Arthur I Cederbaum, Joel T Dudley, Bryan C Fuchs, Youngmin A Lee, Yujin Hoshida, Scott L Friedman
We have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28150521/drug-repurposing-and-therapeutic-anti-microrna-predictions-for-inhibition-of-oxidized-low-density-lipoprotein-induced-vascular-smooth-muscle-cell-associated-diseases
#19
Shun-Tsung Chen, Chien-Hung Huang, Victor C Kok, Chi-Ying F Huang, Jin-Shuei Ciou, Jeffrey J P Tsai, Nilubon Kurubanjerdjit, Ka-Lok Ng
Drug repurposing is a new method for disease treatments, which accelerates the identification of new uses for existing drugs with minimal side effects for patients. MicroRNA-based therapeutics are a class of drugs that have been used in gene therapy following the FDA's approval of the first anti-sense therapy. This study examines the effects of oxLDL on vascular smooth muscle cells (VSMCs) and identifies potential drugs and antimiRs for treating VSMC-associated diseases. The Connectivity Map (cMap) database is utilized to identify potential new uses of existing drugs...
February 2017: Journal of Bioinformatics and Computational Biology
https://www.readbyqxmd.com/read/28139721/therapeutic-properties-of-scutellaria-baicalensis-in-db-db-mice-evaluated-using-connectivity-map-and-network-pharmacology
#20
Bu-Yeo Kim, Kwang Hoon Song, Chi-Yeon Lim, Su-In Cho
We have reported that an extract of Scutellaria baicalensis (ESB) has effects against obesity and hypertriglyceridemia in type 2 diabetic animal model (db/db mouse). In the present study, we tried to explain the pharmacological effects of ESB by integrating gene expression information from db/db mouse liver with that of ESB-treated HepG2 hepatocellular carcinoma cells. Using Connectivity Map (cmap) analysis, we found an inverse relationship in the pharmaceutical profiles based on gene expression between db/db mouse liver and ESB-treated HepG2 cells...
January 31, 2017: Scientific Reports
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