Funding Opportunity PAR-18-864 from the NIH Guide for Grants and Contracts. The National Eye Institute (NEI) supports investigator-initiated, complex, multi-center and other high resource risk epidemiologic studies under the cooperative agreement mechanism, UG1 activity code. Specifically, the purpose of this Funding Opportunity Announcement (FOA) is to support new and innovative ocular epidemiology research.

Notice NOT-DA-18-028 from the NIH Guide for Grants and Contracts

Notice NOT-DK-18-019 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-209 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-18-859 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement is to support research activities that will advance NIAIDs mission to develop a universal influenza vaccine providing durable protection against multiple influenza strains, including efforts to: 1) improve understanding of transmission, natural history and pathogenesis of influenza virus infection; 2) characterize influenza immunity and correlates of immune protection; and 3) support rational design of universal influenza vaccines. This FOA uses the R01 grant mechanism, while the companion FOA, PA-XX-xxx , uses the R21 mechanism. Applicants with preliminary data and/or planning longer-term studies may wish to apply using the R01 mechanism. High risk/high payoff projects that lack preliminary data or utilize existing data may be most appropriate for the R21 mechanism. .

Funding Opportunity PA-18-858 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement is to support research activities that will advance NIAIDs mission to develop a universal influenza vaccine providing durable protection against multiple influenza strains, including efforts to: 1) improve understanding of transmission, natural history and pathogenesis of influenza virus infection; 2) characterize influenza immunity and correlates of immune protection; and 3) support rational design of universal influenza vaccines. This FOA uses the R21 grant mechanism, while the companion FOA, PA-XX-xxx , uses the R01 mechanism. High risk/high payoff projects that lack preliminary data or utilize existing data may be most appropriate for the R21 mechanism. Applicants with preliminary data and/or planning longer-term studies may wish to apply using the R01 mechanism.

Notice NOT-OH-18-010 from the NIH Guide for Grants and Contracts

Notice NOT-HG-18-010 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-211 from the NIH Guide for Grants and Contracts

Notice NOT-DA-18-026 from the NIH Guide for Grants and Contracts

Notice NOT-DA-18-025 from the NIH Guide for Grants and Contracts

39 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/07/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/07/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

In Vitro and In Vivo Activity of Amiodarone Against Ebola Virus.

J Infect Dis. 2018 Jul 16;:

Authors: Dyall J, Johnson JC, Hart BJ, Postnikova E, Cong Y, Zhou H, Gerhardt DM, Michelotti J, Honko AN, Kern S, DeWald LE, O'Loughlin KG, Green CE, Mirsalis JC, Bennett RS, Olinger GG, Jahrling PB, Hensley LE

Abstract
At the onset of the 2013-2016 epidemic of Ebola virus disease (EVD), no vaccine or antiviral medication was approved for treatment. Therefore, considerable efforts were directed towards the concept of drug repurposing or repositioning. Amiodarone, an approved multi-ion channel blocker for the treatment of cardiac arrhythmia, was reported to inhibit filovirus entry in vitro. Compassionate use of amiodarone in EVD patients indicated a possible survival benefit. In support of further clinical testing, we confirmed anti-Ebola virus activity of amiodarone in different cell types. Despite promising in vitro results, amiodarone failed to protect guinea pigs from a lethal dose of Ebola virus.

PMID: 30016444 [PubMed - as supplied by publisher]

Related Articles

Cell-line dependent antiviral activity of sofosbuvir against Zika virus.

Antiviral Res. 2017 Oct;146:161-163

Authors: Mumtaz N, Jimmerson LC, Bushman LR, Kiser JJ, Aron G, Reusken CBEM, Koopmans MPG, van Kampen JJA

Abstract
The recent epidemic of Zika virus (ZIKV) in the Americas and its association with fetal and neurological complications has shown the need to develop a treatment. Repurposing of drugs that are already FDA approved or in clinical development may shorten drug development timelines in case of emerging viral diseases like ZIKV. Initial studies have shown conflicting results when testing sofosbuvir developed for treatment of infections with another Flaviviridae virus, hepatitis C virus. We hypothesized that the conflicting results could be explained by differences in intracellular processing of the compound. We assessed the antiviral activity of sofosbuvir and mericitabine against ZIKV using Vero, A549, and Huh7 cells and measured the level of the active sofosbuvir metabolite by mass spectrometry. Mericitabine did not show activity, while sofosbuvir inhibited ZIKV with an IC50 of ∼4 μM, but only in Huh7 cells. This correlated with differences in intracellular concentration of the active triphosphate metabolite of sofosbuvir, GS-461203 or 007-TP, which was 11-342 times higher in Huh7 cells compared to Vero and A549 cells. These results show that a careful selection of cell system for repurposing trials of prodrugs is needed for evaluation of antiviral activity. Furthermore, the intracellular levels of 007-TP in tissues and cell types that support ZIKV replication in vivo should be determined to further investigate the potential of sofosbuvir as anti-ZIKV compound.

PMID: 28912011 [PubMed - indexed for MEDLINE]

Related Articles

Repurposing metformin for the prevention of cancer and cancer recurrence.

Diabetologia. 2017 Sep;60(9):1639-1647

Authors: Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG

Abstract
Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials. Although repurposing drugs with excellent safety profiles is an appealing strategy for cancer prevention and treatment in the adjuvant setting, there is no substitute for well-executed, large randomised clinical trials to define efficacy and determine the populations that are most likely to benefit from an intervention. Thus, enthusiasm remains for understanding the role of metformin in cancer through ongoing clinical research.

PMID: 28776080 [PubMed - indexed for MEDLINE]

Related Articles

Reconstructing normality following the diagnosis of a childhood chronic disease: does "rare" make a difference?

Eur J Pediatr. 2018 Apr;177(4):489-495

Authors: Germeni E, Vallini I, Bianchetti MG, Schulz PJ

Abstract
Living with a childhood chronic disease can be challenging, especially if the diagnosis involves a rare condition. This study sought to elucidate how the diagnosis of a rare disease, as compared to a common, chronic condition, may influence maternal experiences of childhood illness. We conducted face-to-face, semi-structured interviews with 26 mothers of children treated in a pediatric hospital in the province of Lecco, Italy. Half of the participants had a child diagnosed with Bartter syndrome (BS), and the rest had a child suffering from celiac disease (CD). Interviews were recorded, transcribed, and analyzed using an inductive thematic approach. We identified three main themes from the analysis of our data: (1) disrupted normality and the need to know, (2) reconstructing normality, and (3) acting "normal." Although most participants experienced the disclosure of diagnosis as a relief, processes that facilitated normality reconstruction in celiac families, notably access to appropriate information, social support, and personal contact with comparison others, were found to be important stressors for mothers living with BS.
CONCLUSION: This comparative qualitative study provides evidence on how well-known problems associated with the rarity of childhood diseases impact on families' efforts to cope with the illness and regain a sense of normality. What is Known: • Families living with a rare disease have been found to experience a range of common problems, directly linked to the rarity of these pathologies. What is New: • Maximization of both emotional and instrumental social support, through provision of appropriate information or establishment of disease-specific support groups, could greatly contribute to rare disease families' efforts to cope with childhood illness and regain a sense of normality.

PMID: 29335841 [PubMed - indexed for MEDLINE]

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An unusually large osteochondroma of the mandibular angle: a case report.

World J Surg Oncol. 2017 Nov 13;15(1):201

Authors: Abe R, Miyamoto I, Sato H, Saitou D, Yamaya G, Yamada H

Abstract
BACKGROUND: Osteochondroma is a benign bone tumor that can occur in both the mesenchymal and craniofacial bones. However, craniofacial osteochondromas are extremely rare, because the mandible develops by intramembranous ossification rather than by endochondral ossification.
CASE PRESENTATION: The most common site of craniofacial osteochondroma is the mandibular condyle, followed by the coronoid process. In the present study, we have described the case of a 64-year-old Japanese man with an unusually large osteochondroma located on the internal angle of the mandibular body. Clinical, radiological, pathological, and treatment-related aspects are discussed with respect to the tumor origins.
CONCLUSIONS: In the medical literature, there have been few reports of large osteochondromas of the mandibular angle with no clinical symptoms.

PMID: 29132383 [PubMed - indexed for MEDLINE]

Related Articles

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

Hum Mutat. 2018 Jan;39(1):23-39

Authors: Marsh APL, Edwards TJ, Galea C, Cooper HM, Engle EC, Jamuar SS, Méneret A, Moutard ML, Nava C, Rastetter A, Robinson G, Rouleau G, Roze E, Spencer-Smith M, Trouillard O, Billette de Villemeur T, Walsh CA, Yu TW, IRC5 Consortium, Heron D, Sherr EH, Richards LJ, Depienne C, Leventer RJ, Lockhart PJ

Abstract
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

PMID: 29068161 [PubMed - indexed for MEDLINE]

β-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals.

J Neuropathol Exp Neurol. 2018 Jul 16;:

Authors: Wu HY, Kuo PC, Wang YT, Lin HT, Roe AD, Wang BY, Han CL, Hyman BT, Chen YJ, Tai HC

Abstract
A synergy between β-amyloid (Aβ) and tau appears to occur in Alzheimer disease (AD), but the mechanisms of interaction, and potential locations, are little understood. This study investigates the possibility of such interactions within the cortical synaptic compartments of APP/PS1 mice. We used label-free quantitative mass spectrometry to study the phosphoproteome of synaptosomes, covering 2400 phosphopeptides and providing an unbiased survey of phosphorylation changes associated with amyloid pathology. Hyperphosphorylation was detected on 36 synaptic proteins, many of which are associated with the cytoskeleton. Importantly, tau is one of the most hyperphosphorylated proteins at the synapse, upregulated at both proline-directed kinase (PDK) sites (S199/S202, S396/S404) and nonPDK sites (S400). These PDK sites correspond to well-known pathological tau epitopes in AD patients, recognized by AT8 and PHF-1 antibodies, respectively. Hyperphosphorylation at S199/S202, a rarely examined combination, was further validated in patient-derived human synaptosomes by immunoblotting. Global surveys of upregulated phosphosites revealed 2 potential kinase motifs, which resemble those of cyclin-dependent kinase 5 (CDK5, a PDK) and casein kinase II (CK2, a nonPDK). Our data demonstrate that, within synaptic compartments, amyloid pathology is associated with tau hyperphosphorylation at disease-relevant epitopes. This provides a plausible mechanism by which Aβ promotes the spreading of tauopathy.

PMID: 30016458 [PubMed - as supplied by publisher]