Identification of novel therapeutics for complex diseases from genome-wide association data

Background: Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials. Methods. We previously used Gentrepid (http://www.gentrepid.org) as a platform to predict 1,497 candidate genes for the seven complex diseases considered in the Wellcome Trust Case-Control Consortium genome-wide association study; namely Type 2 Diabetes, Bipolar Disorder, Crohn's Disease, Hypertension, Type 1 Diabetes, Coronary Artery Disease and Rheumatoid Arthritis. Here, we adopted a simple approach to integrate drug data from three publicly available drug databases: the Therapeutic Target Database, the Pharmacogenomics Knowledgebase and DrugBank; with candidate gene predictions from Gentrepid at the systems level. Results: Using the publicly available drug databases as sources of drug-target association data, we identified a total of 428 candidate genes as novel therapeutic targets for the seven phenotypes of interest, and 2,130 drugs feasible for repositioning against the predicted novel targets. Conclusions: By integrating genetic, bioinformatic and drug data, we have demonstrated that currently available drugs may be repositioned as novel therapeutics for the seven diseases studied here, quickly taking advantage of prior work in pharmaceutics to translate ground-breaking results in genetics to clinical treatments. © 2014 Grover et al.; licensee BioMed Central Ltd

Novel therapeutics for coronary artery disease from genome-wide association study data

BACKGROUND: Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD. METHODS: Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (http://www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatic modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD. RESULTS: Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05). CONCLUSIONS: We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies

Insulin-like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation

BackgroundThe early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life.MethodsWe used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed.ResultsAd-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (PConclusionsAntiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F.; Drogemuller, Chris J.; Coates, P. Toby H

Gene therapy to improve pancreatic islet transplantation for type 1 diabetes mellitus

Pancreatic islet transplantation is a promising treatment option for Type 1 Diabetics, offering improved glycaemic control through restoration of insulin production and freedom from life-threatening hypoglycaemic episodes. Implementation of the Edmonton protocol in 2000, a glucocorticoid-free immunosuppressive regimen has led to improved islet transplantation success. >50% of islets are lost post-transplantation primarily through cytokine-mediated apoptosis, ischemia and hypoxia. Gene therapy presents a novel strategy to modify islets for improved survival post-transplantation. Current islet gene therapy approaches aim to improve islet function, block apoptosis and inhibit rejection. Gene transfer vectors include adenoviral, adeno-associated virus, herpes simplex virus vectors, retroviral vectors (including lentiviral vectors) and non-viral vectors. Adeno-associated virus is currently the best islet gene therapy vector, due to the vectors minimal immunogenicity and high safety profile. In animal models, using viral vectors to deliver genes conferring local immunoregulation, anti-apoptotic genes or angiogenic genes to islets can significantly improve islet survival in the early post-transplant period and influence long term engraftment. With recent improvements in gene delivery and increased understanding of the mechanisms underlying graft failure, gene therapy for islet transplantation has the potential to move closer to the clinic as a treatment for patients with Type 1 Diabetes.Hughes, Amy; Jessup, Claire; Drogemuller, Chris; Mohanasundaram, Daisy; Milner, Clyde; Rojas, Darling; R. Russ, Graeme; and T.H. Coates, Patric

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Not AvailableLac insect, Kerria lacca are placed under the order Hemiptera, superfamily Coccoidea, family Tachardiidae. They are characterized by the presence of a special type of mouth-parts, called the sucking type, intended for sucking plant juices- this is the sole mode of their feeding. The voyage of life of lac insects begins with completion of embryonic development within the body of the mother when eggs change their position in the ovariole. Eggs then travel through oviducts and come out of the and resinous cell. Hatching of eggs mostly takes place before reaching the incubation chamber has called as viviparity.Not Availabl

Effect of Newer Pesticide Schedules on the Population of Sucking Pests and Predators on Okra

Not AvailableA field study was carried out to determine the efficacy of different treatment schedules against major sucking pests viz., leafhoppers, whitefly and red spider mite and their predators on okra, Abelmoschus esculentus (L.) Moench during the kharif 2008 and 2009. Each treatment comprised three sprays; first spray was given 35 d after seed sowing and thereafter at 15 d intervals, except treatment 9 where seed treatment was done and two sprays were given along with 2nd and 3rd spray as in rest other treatments. The results showed that thiamethoxam 20 g a.i/ha, fipronil 50 g a.i/ha and endosulfan @ 700 g a.i/ha effectively reduced the sucking pests viz., leafhopper, whitefly and red spider mite population during 1st, 2nd, and 3rd sprays over two seasons, respectively. The activity of insect predatory population (coccinellids and spiders) in treatment schedules T1 and T3 comprising of Neemazal/ Econeem @ 2ml/L, emamectin benzoate @ 10 g a.i/ha and endosulfan @ 700 g a.i/ha were found to be at par with untreated check indicating non-hazardous to these predominant natural enemies in okra ecosystem.Not Availabl

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Not Availableप्रोपोलिस मोम और रेजिन की विभिन्न मात्राओ का एक मिश्रण है जो मधुमक्खियों द्वारा पौधों विशेषकर फूल और कलियों से एकत्र कर बनाया जाता हैं। मधुमक्खिया उनके मेन्डिबल्स से फूल और कलियों के सुरक्षात्मक रेजिन को स्क्रैप कर फिर उसे अपने पिछले पैरों से पराग छर्रों की तरह हाइव तक ले जाया जाता है। यह माना जा सकता है कि, रेजिन इकट्ठा करने और मॉडलिंग की प्रक्रिया में मधुमक्खियों द्वारा लार और अन्य स्राव के साथ ही मोम भी मिश्रित कर दिया जाता हैं। श्रमिक मक्खियों द्वारा इस रेजिन का प्रयोग नेस्ट केविटीज के अंदर छिद्र भरने के लिए और सभी ब्रूड छ्त्ते की मरम्मत, छ्त्ते में छोटे दरारें सील करने, हाइव के प्रवेश द्वार का आकार कम करने, छ्त्ते के अंदर किसी भी मरे हुए जानवर को सील बंद करने में, छ्त्ते के प्रवेश द्वार के आकार को कम करने के लिये एवं शायद सबसे महत्वपूर्ण शिशु (ब्रूड) कक्षों को सील करने के लिए, मोम के साथ प्रोपोलिस की थोड़ी सी मात्रा मिश्रित कर किया जाता है। ये उपयोग प्रोपोलिस के जीवाणुरोधी और ऐंटिफंगल प्रभाव होने के कारण कॉलोनी की बीमारियों के विरुद्ध रक्षा करते हैं। प्रोपोलिस का संघटन मधुमक्खियों के लिए उपलब्ध पौधों के प्रकार पर निर्भर करता है। प्रोपोलिस का रंग, गंध एवं औषधीय विशेषताएँ साल के मौसम एवं स्रोत के अनुसार परिवर्तित होते रहते है। इसके अलावा, कुछ मधुमक्खियाँ एवं कुछ कालोनियाँ प्रोपोलिस के अधिक उत्साही संग्राहक होते हैं, जो कि आमतौर पर मधुमक्खी-पालक के लिए निराशात्मक होता है, क्योंकि प्रोपोलिस एक बहुत चिपचिपा पदार्थ होता है, अत: बहुतायत में होने पर यह बक्से से फ्रेम को निकालने में कठिनाई कर देता हैं। प्रोपोलिस के लिए फ़ोरेजिगं केवल वेस्टर्न मधुमक्खी एपिस मेलिफ़ेरा में ही पाई जाती है। एपिस की एशियाई प्रजाति प्रोपोलिस जमा नहीं करती हैं। केवल मेलिपोनिनी या बेडंक मधुमक्खियाँ ही हीव्स को सील करने, शहद एवं भंडारण हेतु पराग घट निर्माण के लिए, इसी प्रकार का चिपचिपा राल पदार्थ एकत्रित करने के लिए जानी जाती है।Not Availabl

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Not AvailableA new species of lac insect (Hemiptera: Coccomorpha: Tachardiidae), Kerria canalis Rajgopal sp. nov., collected from Rain Tree, Samanea saman (Jacq.) Merr. (Fabaceae), from India (Tamil Nadu, Madurai), is described and illustrated. Detailed line diagrams and photographs, and a key for the identification of all known Kerria species are provided. Variations in the taxonomic characters of K. canalis and its congeners are discussed.Not Availabl

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