Funding Opportunity PAR-17-276 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA), issued by NINDS, is to invite currently awarded NIH StrokeNet centers and potential new stroke centers to participate as a Regional Coordinating Stroke Center in the NIH StrokeNet clinical trials network. The goal of this existing network is to maximize efficiencies to develop, promote and conduct high-quality, multi-site clinical trials focused on key interventions in stroke prevention, treatment, and recovery with the objective to have a balanced portfolio between all three approaches. Exploratory Phase 1/2 and confirmatory Phase 3 clinical trials as well as biomarker-validation studies that are immediately preparatory to trials will be coordinated through separate National Clinical Coordinating (NCC) and National Data Management Centers (NDMC).

Funding Opportunity PAR-17-275 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose exploratory and confirmatory clinical trials focused on promising interventions, as well as biomarker-or outcome measure validation studies that are immediately preparatory to trials in stroke prevention, treatment, and recovery. The program will utilize the cooperative agreement mechanism to enable milestone-drive projects.

Funding Opportunity PAR-17-277 from the NIH Guide for Grants and Contracts. This FOA encourages requests for access to research resources for multi-site exploratory and confirmatory clinical trials focused on promising interventions, as well as biomarker-or outcome measure validation studies that are immediately preparatory to trials in stroke prevention, treatment, and recovery. Successful applicants will be given access to the NIH StrokeNet infrastructure. Following peer review, NINDS will prioritize trials among the highest scoring to be conducted in the NIH StrokeNet infrastructure. The NIH StrokeNet National Coordinating Center (NCC) will work with the successful applicant to implement the proposed study efficiently and the National Data Management Center (NDMC) will provide statistical and data management support. The NIH StrokeNet Regional Coordinating Centers (RCCs) and their affiliated clinical sites will provide recruitment/retention support as well as on-site implementation of the clinical protocol.

Funding Opportunity PAR-17-274 from the NIH Guide for Grants and Contracts. This FOA encourages applications for multi-site exploratory and confirmatory clinical trials focused on promising interventions, as well as biomarker-or outcome measure validation studies that are immediately preparatory to trials in stroke prevention, treatment, and recovery. Successful applicants will collaborate and conduct the trial within the NIH StrokeNet. Following peer review, NINDS will prioritize trials among the highest scoring to be conducted in the NIH StrokeNet infrastructure. The NIH StrokeNet National Coordinating Center (NCC) will work with the successful applicant to implement the proposed study efficiently and the National Data Management Center (NDMC) will provide statistical and data management support. The NIH StrokeNet Regional Coordinating Centers (RCCs) and their affiliated clinical sites will provide recruitment/retention support as well as on-site implementation of the clinical protocol.

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Related Articles

Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview.

Adv Ther. 2017 May 08;:

Authors: Wen WX, Lee SY, Siang R, Koh RY

Abstract
Fibrosis is a potentially debilitating disease with high morbidity rates. It is estimated that half of all deaths that occur in the USA are attributed to fibrotic disorders. Fibrotic disorders are characterized primarily by disruption in the extracellular matrix deposition and breakdown equilibrium, leading to the accumulation of excessive amounts of extracellular matrix. Given the potentially high prevalence of fibrosis and the paucity of agents currently available for the treatment of this disease, there is an urgent need for the identification of drugs that can be utilized to treat the disease. Pentoxifylline is a methylxanthine derivative that is currently approved for the treatment of vascular diseases, in particular, claudication. Pentoxifylline has three main properties: improving the rheological properties of blood, anti-inflammatory, and antioxidative. Recently, the effectiveness of pentoxifylline in the treatment of fibrosis via attenuating and reversing fibrotic lesions has been demonstrated in several clinical trials and animal studies. As a result of the limited availability of antifibrotic agents in the long-term treatment of fibrosis that can attenuate and even reverse fibrotic lesions effectively, it would be of particular importance to consider the potential clinical utility of pentoxifylline in the treatment of fibrosis. Thus, this paper discusses the evolving roles of pentoxifylline in the treatment of different types of fibrosis.

PMID: 28484954 [PubMed - as supplied by publisher]

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Pediatric Drug Nitazoxanide: A Potential Choice for Control of Zika.

Open Forum Infect Dis. 2017;4(1):ofx009

Authors: Cao RY, Xu YF, Zhang TH, Yang JJ, Yuan Y, Hao P, Shi Y, Zhong J, Zhong W

Abstract
Zika virus (ZIKV) infection can be the cause of congenital malformations, including microcephaly in infants and can cause other disorders such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, which can also occur in some infected adults. However, at this time, there is no drug approved to treat ZIKV infection. Drug repurposing is the promptest way to obtain an effective drug during a global public health emergency such as the spread of Zika virus. In this study, we report a US Food and Drug Admistration-approved drug that is safe for pediatric use. Nitazoxanide and its bioactive metabolite, tizoxanide, have anti-ZIKV potential in vitro, and we identified that they exerts antiviral effect possibly by targeting the viral postattachment step.

PMID: 28480282 [PubMed - in process]

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Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Biochem Biophys Res Commun. 2017 May 02;:

Authors: Xiao ZX, Chen RQ, Hu DX, Xie XQ, Yu SB, Chen XQ

Abstract
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.

PMID: 28476618 [PubMed - as supplied by publisher]

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In vitro activity of the antiasthmatic drug zafirlukast against the oral pathogens Porphyromonas gingivalis and Streptococcus mutans.

FEMS Microbiol Lett. 2017 Jan 01;364(2):

Authors: Gerits E, Van der Massen I, Vandamme K, De Cremer K, De Brucker K, Thevissen K, Cammue BPA, Beullens S, Fauvart M, Verstraeten N, Michiels J, Roberts M

Abstract
Oral infections are among the most common diseases worldwide. Many protocols for the prevention and treatment of oral infections have been described, yet no golden standard has been developed so far. The antiseptic chlorhexidine and antibiotics are often used in these treatment procedures. However, long-term use of chlorhexidine can lead to side effects and extensive use of antibiotics can promote the development of antibiotic-resistant bacteria, which in turn can compromise the effectiveness of the treatment. Consequently, it remains important to search for new antibacterial agents for the treatment of oral infections. In this study, we report on the antibacterial activity of the antiasthma drug zafirlukast against oral pathogens Porphyromonas gingivalis and Streptococcus mutans. Furthermore, its activity against oral biofilms grown on titanium surfaces was confirmed. In addition, we demonstrated that zafirlukast displays no cytotoxicity against human osteoblasts. Combined, this study paves the way for further research to determine the potential of zafirlukast to be used as a new antibiotic against oral pathogens.

PMID: 28087617 [PubMed - indexed for MEDLINE]

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Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii.

J Antibiot (Tokyo). 2016 Jun;69(6):415-21

Authors: Tran TB, Cheah SE, Yu HH, Bergen PJ, Nation RL, Creek DJ, Purcell A, Forrest A, Doi Y, Song J, Velkov T, Li J

Abstract
Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii. However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of polymyxin B with anthelmintic closantel against A. baumannii. Closantel monotherapy (16 mg l(-1)) was ineffective against most tested A. baumannii isolates. However, closantel at 4-16 mg l(-1) with a clinically achievable concentration of polymyxin B (2 mg l(-1)) successfully inhibited the development of polymyxin resistance in polymyxin-susceptible isolates, and provided synergistic killing against polymyxin-resistant isolates (MIC ⩾4 mg l(-1)). Our findings suggest that the combination of polymyxin B with closantel could be potentially useful for the treatment of MDR, including polymyxin-resistant, A. baumannii infections. The repositioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial 'superbugs'.

PMID: 26669752 [PubMed - indexed for MEDLINE]

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Three Cases of Erdheim-Chester Disease With Intraocular Manifestations: Imaging and Histopathology Findings of a Rare Entity.

Am J Ophthalmol. 2017 Apr;176:141-147

Authors: Tan AC, Yzer S, Atebara N, Marr BP, Verdijk RM, Dalm VA, Freund KB, Yannuzzi L, Missotten T

Abstract
PURPOSE: To report intraocular manifestations of Erdheim-Chester Disease (ECD) with multimodal imaging.
DESIGN: A retrospective observational case series.
METHODS: This was a multicenter case series of 3 patients with confirmed tissue diagnosis of ECD that showed intraocular manifestations and were imaged at baseline and follow-up visits.
RESULTS: Intraocular manifestations are rarely observed in association with ECD. Intraocular manifestations of ECD seen on multimodal imaging include histiocytic choroidal infiltration causing choroidal lesions, complicated by recurrent serous retinal detachment (SRD). Short-term resolution of SRD was observed with ocular therapies including intravitreal injections of anti-vascular endothelial growth factor or verteporfin photodynamic therapy in combination with systemic chemotherapy therapies and oral corticosteroids; however, recurrences were common. Chorioretinal biopsy confirmed the diagnosis of ECD in 1 case, with the presence of histiocytic infiltration, fibrosis, and characteristic immunohistologic staining. In another case, with a novel ARAF positive mutation, treatment with sorafenib showed regression of the choroidal lesions and resolution of the SRD on multimodal imaging. These lesions were previously resistant to other forms of therapy.
CONCLUSIONS: Rare intraocular manifestations of ECD confirmed on histopathology can be imaged with multimodal imaging. We report 3 cases, including 1 case diagnosed through histology from chorioretinal biopsy and another case associated with a novel ARAF mutation responsive to targeted therapy with sorafenib. The identification of novel somatic mutation associated with ECD enabled treatment with a new-targeted systemic agent. Multimodal imaging in these cases can also be used to monitor response to therapy.

PMID: 28153505 [PubMed - indexed for MEDLINE]

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Perforation With Submucosal Cleft Palate in a Previously Undiagnosed Adult Patient.

J Craniofac Surg. 2016 Oct;27(7):e659-e661

Authors: Evin ŞG, Karamese M, Akdag O, Selimoglu MN, Tosun Z

Abstract
Perforation with a submucosal cleft palate (SMCP) is a rare condition with a limited number of cases reported in the literature. However, most described cases include neonates and infants, but not cases due to trauma or infection. Here, we present a case of an adult patient with SMCP with a perforation of the palate who was undiagnosed. In light of this case, diagnosis and treatment of perforation in SMCP are presented. A new diagram that can be used in the management of these patients with velopharyngeal insufficiency is proposed.

PMID: 27526237 [PubMed - indexed for MEDLINE]

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Pharmacotherapy of inborn errors of metabolism illustrating challenges in orphan diseases.

J Pharmacol Toxicol Methods. 2016 Sep-Oct;81:9-14

Authors: Das AM

Abstract
Orphan diseases (OD) have special challenges based on the rarity of the conditions. Mostly multicentre studies are required, controlled studies are difficult to perform. Based on the often chronic course of OD with slow progress the effect of therapeutic interventions is difficult to assess. Development and production of pharmaceutical substances for OD is difficult, time-consuming and sophisticated. Special incentives by the regulatory bodies like protocol assistance, long marketing exclusivity and reduced licencing fees encourage the development of orphan drugs. Inborn errors of metabolism (IEMs) due to enzyme or transporter deficiencies are taken as an example for OD. Accumulation of substrates proximal to the deficient enzyme during catabolic episodes leads to autointoxication with acute onset of symptoms. IEMs due to transporter deficiency usually have a more stable, chronic course. Therapeutic options are substrate reduction by diet or drugs, vitamin/cofactor supplementation, enzyme replacement, enzyme augmentation and transplantation of organs or cells. Phenylketonuria (PKU) is the prototype of an IEM which can be successfully treated by diet. The outcome of hepatorenal tyrosinaemia type 1 was revolutionarized by substrate reduction using nitisinone (NTBC) which was discovered by chance. Lysosomal storage diseases are examples where enzyme replacement therapy is successful. Enzyme augmentation can be achieved in some IEM-patients with a mild phenotype (residual enzyme activity) by chaperones which stabilize the enzyme. Organ transplantation is an option in those patients who cannot be managed by drugs and/or diet. Bone marrow transplantation is successful in some patients where CNS-involvement occurs. The CNS cannot be reached by enzyme replacement therapy (blood-brain barrier). While safety and efficacy of drugs for OD have been demonstrated pre-marketing, post-marketing surveys are often necessary to include more patients.

PMID: 26921514 [PubMed - indexed for MEDLINE]

Related Articles

A Web Based Tool to Enhance Monitoring and Retention in Care for Tuberculosis Affected Patients.

Stud Health Technol Inform. 2017;237:204-208

Authors: Giannini B, Riccardi N, Di Biagio A, Cenderello G, Giacomini M

Abstract
Tuberculosis (TB) is responsible for a global epidemic. TB treatment requires long-term therapy usually with multiple drugs, which have potential side effects and interactions that may influence patients' adherence to treatment. The TB Ge network is a multi-centric web based platform that collects clinical information of TB affected patients to increase their support and retention in care. The system stores the list of all tuberculosis episodes for each patient with the related data, starting from the first visit including follow-ups clinical evaluations, laboratory tests, imaging and therapies. Data can be manually input through the web interface or can be automatically imported from hospitals Laboratory Information Systems without human intervention. Automatic data import enhances data reuse and prevents errors introduction and time wasting. The network is an implementation of the Healthcare Services Specification Project (HSSP), as the Retrieve, Locate, and Update Service (RLUS) is used to manage patients' data. Clinical data are shared through standard HL7 Clinical Document Architecture (CDA) documents. Semantic interoperability is granted by the adoption of LOINC and ATC codes.

PMID: 28479569 [PubMed - in process]

Notice NOT-CA-17-057 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-OD-17-009 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite research project applications to support biomedical and behavioral research that will provide scientific data to inform regulation of tobacco products to protect public health. Research Projects must address the research priorities related to the regulatory authority of the Food and Drug Administration (FDA) Center for Tobacco Products (CTP). The awards under this FOA will be administered by NIH using funds that have been made available through FDA CTP and the Family Smoking Prevention and Tobacco Control Act (P.L. 111-31). Research results from this FOA are expected to generate findings and data that are directly relevant in informing the FDA's regulation of the manufacture, distribution, and marketing of tobacco products to protect public health.