Funding Opportunity RFA-AR-18-004 from the NIH Guide for Grants and Contracts. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) requests applications for the NIAMS Resource-based Centers Program (P30) for rheumatic diseases research areas within its mission. The Resource-based Centers will provide critical research infrastructure, shared facilities, services, and/or resources to groups of investigators conducting research on rheumatic diseases, enabling them to conduct their independently-funded individual and/or collaborative research projects more efficiently and/or more effectively, with the broad overall goal of accelerating, enriching, and enhancing the effectiveness of ongoing basic, translational, and clinical research and promoting new research within the NIAMS mission.

Funding Opportunity RFA-MH-18-251 from the NIH Guide for Grants and Contracts. This Limited Competition Funding Opportunity Announcement (FOA) invites one application to continue the activities of the Data Coordinating Center (DCC) of the National NeuroAIDS Tissue Consortium as previously funded under RFA-MH-13-071. The DCC will function as part of the NNTC, a national resource that provides clinical data and biological specimens to NeuroAIDS investigators interested in conducting research toward a cure of Human Immunodeficiency Virus (HIV-1) infection from the central nervous system (CNS), and research on the neuropathogenesis of HIV-1 induced CNS and peripheral nervous system (PNS) dysfunction in the context of anti-retroviral therapy (ART). The DCC works cooperatively with the NNTC-affiliated clinical sites to provide the following: 1) management and database capabilities to ensure effective clinical and brain banking operations, and to serve as the data repository for the NNTC; 2) scientific expertise in biostatistics and HIV-1 epidemiology to enable broad analyses of the NNTC clinical database, and to aid in statistical analysis of recruitment and retention goals for the clinical sites affiliated with the NNTC; and 3) expanding the capability to include coordinating the distribution of data and specimens stored at other national and international clinical sites to ensure that NeuroAIDS investigators have access to CNS and PNS resources that are difficult to obtain from HIV-1 infected individuals across the lifespan. The clinical sites affiliated with the NNTC will have all patient contact which will include all clinical assessments ante mortem. The clinical sites will also be responsible for the collection and housing of post mortem clinical specimens. The DCC will serve as a NeuroAIDS data repository which will include the clinical assessment data and data obtained post mortem including brain pathology reports, laboratory tests conducted on the collected specimens/fluids, a comprehensive inventory of those specimens housed at each clinical site, and research data, such as bioinformatics datasets. A limited competition application for the NNTC DCC is being sought under a separate but related companion FOA (RFA-MH-18-250)

Funding Opportunity RFA-MH-18-250 from the NIH Guide for Grants and Contracts. This Limited Competition Funding Opportunity Announcement (FOA) invites applications to continue the activities of the National NeuroAIDS Tissue Consortium (NNTC) Clinical Sites as previously funded under RFA-MH-13-070. The NNTC Clinical Sites will function as part of the NNTC, a national resource that provides clinical data and biological specimens to NeuroAIDS investigators interested in conducting research toward a cure of Human Immunodeficiency Virus (HIV-1) infection from the central nervous system (CNS), and research on the neuropathogenesis of HIV-1 induced CNS and peripheral nervous system (PNS) dysfunction in the context of anti-retroviral therapy (ART). The NNTC Clinical Sites collect neuromedical and neuropsychiatric data from late stage, HIV-1 infected subjects who have indicated a willingness to participate in organ donation. The NNTC Clinical Sites are responsible for the following: 1) recruitment, clinical assessment and follow-up of the late-stage NNTC cohort; and 2) collection, maintenance and distribution of specimen resources. All data generated from these activities are transferred to the NNTC Data Coordinating Center (DCC). The NNTC Clinical Sites work cooperatively with the DCC to provide the clinical data and specimen resources to research investigators. A limited competition for the NNTC DCC is being sought under a separate but related companion FOA (RFA-MH-18-251).

Funding Opportunity PA-17-259 from the NIH Guide for Grants and Contracts. The NICHD Exploratory/Developmental Grant program supports exploratory and developmental research projects that fall within the NICHD mission by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

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

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/04/19

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.

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

pharmacogenomics

These pubmed results were generated on 2017/04/19

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.

35 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 2017/04/19

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.

Drug Repurposing Patent Applications October-December 2016.

Assay Drug Dev Technol. 2017 Apr;15(3):120-126

Authors: Mucke HAM

PMID: 28418694 [PubMed - in process]

Validating the Predicted Effect of Astemizole and Ketoconazole Using a Drosophila Model of Parkinson's Disease.

Assay Drug Dev Technol. 2017 Apr;15(3):106-112

Authors: Styczyńska-Soczka K, Zechini L, Zografos L

Abstract
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically. In this work, we utilize a transgenic Drosophila model of Parkinson's disease, made by expressing human alpha-synuclein in the Drosophila brain, to validate two repurposed compounds: astemizole and ketoconazole. Both have been computationally predicted to have an ameliorative effect on Parkinson's disease, but neither had been tested using an in vivo model of the disease. After treating the flies in parallel, results showed that both drugs rescue the motor phenotype that is developed by the Drosophila model with age, but only ketoconazole treatment reversed the increased dopaminergic neuron death also observed in these models, which is a hallmark of Parkinson's disease. In addition to validating the predicted improvement in Parkinson's disease symptoms for both drugs and revealing the potential neuroprotective activity of ketoconazole, these results highlight the value of Drosophila models of Parkinson's disease as key tools in the context of in vivo drug discovery, drug repurposing, and prioritization of hits, especially when coupled with computational predictions.

PMID: 28418693 [PubMed - in process]

Drug Repurposing Patent Applications January-March 2017.

Assay Drug Dev Technol. 2017 Apr;15(3):127-132

Authors: Mucke HAM

PMID: 28418692 [PubMed - in process]

Related Articles

Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses.

Molecules. 2016 Jun 28;21(7):

Authors: Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA, Verri WA

Abstract
In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.

PMID: 27367653 [PubMed - indexed for MEDLINE]

Improving data workflow systems with cloud services and use of open data for bioinformatics research.

Brief Bioinform. 2017 Apr 16;:

Authors: Karim MR, Michel A, Zappa A, Baranov P, Sahay R, Rebholz-Schuhmann D

Abstract
Data workflow systems (DWFSs) enable bioinformatics researchers to combine components for data access and data analytics, and to share the final data analytics approach with their collaborators. Increasingly, such systems have to cope with large-scale data, such as full genomes (about 200 GB each), public fact repositories (about 100 TB of data) and 3D imaging data at even larger scales. As moving the data becomes cumbersome, the DWFS needs to embed its processes into a cloud infrastructure, where the data are already hosted. As the standardized public data play an increasingly important role, the DWFS needs to comply with Semantic Web technologies. This advancement to DWFS would reduce overhead costs and accelerate the progress in bioinformatics research based on large-scale data and public resources, as researchers would require less specialized IT knowledge for the implementation. Furthermore, the high data growth rates in bioinformatics research drive the demand for parallel and distributed computing, which then imposes a need for scalability and high-throughput capabilities onto the DWFS. As a result, requirements for data sharing and access to public knowledge bases suggest that compliance of the DWFS with Semantic Web standards is necessary. In this article, we will analyze the existing DWFS with regard to their capabilities toward public open data use as well as large-scale computational and human interface requirements. We untangle the parameters for selecting a preferable solution for bioinformatics research with particular consideration to using cloud services and Semantic Web technologies. Our analysis leads to research guidelines and recommendations toward the development of future DWFS for the bioinformatics research community.

PMID: 28419324 [PubMed - as supplied by publisher]

O-Aminobenzoyl-S-Nitrosoglutathione: a Fluorogenic, Cell Permeable, Pseudo-Substrate for S-Nitrosoglutathione Reductase.

Free Radic Biol Med. 2017 Apr 15;:

Authors: Sun BL, Palmer L, Alam SR, Adekoya I, Brown-Steinke K, Periasamy A, Mutus B

Abstract
S-nitrosoglutathione reductase (GSNOR) is a multifunctional enzyme. It can catalyze NADH-dependent reduction of S-nitrosoglutathione (GSNO); as well as NAD(+)-dependent oxidation of hydroxymethylglutathione (HMGSH; an adduct formed by the spontaneous reaction between formaldehyde and glutathione). While initially recognized as the enzyme that is involved in formaldehyde detoxification, increasing amount of research evidence has shown that GSNOR also plays a significant role in nitric oxide mediated signaling through its modulation of protein S-nitrosothiol abundance via transnitrosation reactions with GSNO. In humans, GSNOR/S-nitrosothiols have been implicated in the etiology of several diseases including lung cancer, cystic fibrosis, asthma, pulmonary hypertension, and neuronal dysfunction. Currently, it is not possible to monitor the activity of GSNOR in live cells. In this article, we present a new compound, O-aminobenzoyl-S-nitrosoglutathione (OAbz-GSNO), which acts as a fluorogenic pseudo-substrate for GSNOR with an estimated Km value of 320µM. The weak OAbz-GSNO fluorescence increases by approximately 14 fold upon reduction of its S-NO moiety. In live cell imaging studies, OAbz-GSNO is readily taken up by primary pulmonary endothelial cells and localizes to the same perinuclear region as GSNOR. The perinuclear OAbz-GSNO fluorescence increases in a time dependent manner and this increase in fluorescence is abolished by siRNA knockdown of GSNOR or by treatment with GSNOR-specific inhibitors N6022 and C3. Taken together, these data demonstrate that OAbz-GSNO can be used as a tool to monitor the activity of GSNOR in live cells.

PMID: 28419866 [PubMed - as supplied by publisher]

The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements.

PLoS One. 2017;12(4):e0175486

Authors: Char JE, Dunn C, Davies Z, Milla C, Moss RB, Wine JJ

Abstract
We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR. Measured sweat rates must be corrected for sweat losses. With estimated sweat losses of 0.023 to 0.08 nl·gland-1·min-1, ivacaftor increased the average C-sweat rates 3-7 fold, and estimated function as % of WT were 4.1-12% off ivacaftor and 21.9-32% on ivacaftor (larger values reflect increased loss estimates). Based on single tests, an R117H-7T/ R117H-7T subject showed 6-9% WT function off ivacaftor and 28-43% on ivacaftor. Repeat testing of an R117H-5T/F508del subject detected only trace responding to ivacaftor. We conclude that in vivo, R117H PO is strongly increased by ivacaftor, but channel number, mainly determined by variable deletion of exon 10, has a marked influence on outcomes.

PMID: 28419121 [PubMed - in process]

Inhaled Heparin: Therapeutic Efficacy and Recent Formulations.

J Aerosol Med Pulm Drug Deliv. 2017 Apr 18;:

Authors: Yildiz-Pekoz A, Ozsoy Y

Abstract
Heparin is well known for its anticoagulant and anti-inflammatory properties. Inhaled heparin regimens are increasingly being used to manage lung disease. It has been used to treat cystic fibrosis, thromboembolism, and pulmonary fibrosis, as well as bronchial asthma and asthma-induced airway hypersensitivity. Several preclinical studies attained some useful effects of heparin-administered, parenterally and through inhalation, treatment of lung disease. Besides, recent clinical trials suggest that inhaled heparin for lung diseases is beneficial and safe, but such data remain to be limited. In 2005, the orphan designation was granted by the European Commission for heparin sodium (inhalation use) for the treatment of cystic fibrosis. The positive results of heparin in the pulmonary route necessitate a focus on the preparation and evaluation of heparin in advanced drug delivery systems, namely nano/microparticles and liposomes. Through this pulmonary delivery, heparin is protected from enzymatic degradation within the airway. Heparin is thus passively targeted into the lungs, and long-lasting localized treatment is achieved. On the other hand, these systems have encountered several problems as follows: (1) polymers, such as poly-L-lactide-glycolic acid, poly (lactic acid), and chitosan, used to prepare heparin-loaded microparticle/nanoparticle (MP/NP) systems have not been granted approval for lung application by the FDA and (2) liposomal and NP formulation stability is the main problem of formulation design. We propose that additional in vitro and in vivo research is necessary to assess the clinical applicability of this treatment strategy. The present article discusses heparin treatments for lung diseases and the use of heparin and/or heparin-loaded drugs in advanced delivery systems through the pulmonary route.

PMID: 28418758 [PubMed - as supplied by publisher]

Physical characterization of Tobramycin Inhalation Powder: II. State Diagram of an Amorphous Engineered Particle Formulation.

Mol Pharm. 2017 Apr 18;:

Authors: Miller D, Tan T, Nakamura J, Malcolmson R, Tarara T, Weers J

Abstract
Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI® Podhaler®, a drug/device combination for treatment of cystic fibrosis. A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of relative humidity and temperature. Because, in principle, changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product. Studies included morphological assessments of particles, thermal analysis to measure the gel-to-liquid crystalline phase transition (Tm) of the phospholipid and the glass transition temperature (Tg) of tobramycin sulfate, enthalpy relaxation measurements to estimate structural relaxation times, and gravimetric vapor sorption to measure moisture sorption isotherms of TIP and its components. Collectively, these data enabled development of a state diagram for TIP - a map of the environmental conditions under which physical stability can be expected. This diagram shows that, at long-term storage conditions, TIP is at least 50°C below the Tg of the amorphous phase and at least 40°C below the Tm of the gel phase. Enthalpy relaxation measurements demonstrate that the characteristic structural relaxation times under these storage conditions are many orders of magnitude greater than that at Tg. These data, along with long-term physicochemical stability studies conducted during product development, demonstrate that TIP is physically stable, remaining as a mechanical solid over timescales and conditions relevant to a pharmaceutical product. This met a key design goal in the development of TIP: a room-temperature-stable formulation (three years of shelf-life) that obviates the need for refrigeration for long-term storage. This has enabled development of TOBI Podhaler - an approved inhaled drug product that meaningfully reduces the treatment burden of cystic fibrosis patients worldwide.

PMID: 28418683 [PubMed - as supplied by publisher]

Related Articles

Prophylactic anti-staphylococcal antibiotics for cystic fibrosis.

Cochrane Database Syst Rev. 2017 Apr 18;4:CD001912

Authors: Smyth AR, Rosenfeld M

Abstract
BACKGROUND: Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review.
OBJECTIVES: To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested these hypotheses. Prophylaxis:1. improves clinical status, lung function and survival;2. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis);3. leads to fewer isolates of common pathogens from respiratory secretions;4. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted.Most recent search of the Group's Register: 29 September 2016.
SELECTION CRITERIA: Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity.
DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and methodological quality and extracted data.
MAIN RESULTS: We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence was downgraded based on GRADE assessments and outcome results ranged from moderate to low quality. Downgrading decisions were due to limitations in study design (all outcomes); for imprecision (number of people needing additional antibiotics); and for inconsistency (weight z score).Fewer children receiving anti-staphylococcal antibiotic prophylaxis had one or more isolates of Staphylococcus aureus (low quality evidence). There was no significant difference between groups in infant or conventional lung function (moderate quality evidence). We found no significant effect on nutrition (low quality evidence), hospital admissions, additional courses of antibiotics (low quality evidence) or adverse effects (moderate quality evidence). There was no significant difference in the number of isolates of Pseudomonas aeruginosa between groups (low quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis.
AUTHORS' CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis leads to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.

PMID: 28417451 [PubMed - as supplied by publisher]

Related Articles

Autonomous sweat extraction and analysis applied to cystic fibrosis and glucose monitoring using a fully integrated wearable platform.

Proc Natl Acad Sci U S A. 2017 Apr 17;:

Authors: Emaminejad S, Gao W, Wu E, Davies ZA, Yin Yin Nyein H, Challa S, Ryan SP, Fahad HM, Chen K, Shahpar Z, Talebi S, Milla C, Javey A, Davis RW

Abstract
Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications.

PMID: 28416667 [PubMed - as supplied by publisher]

Related Articles

Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children.

J Cyst Fibros. 2017 Apr 14;:

Authors: Garg M, Leach ST, Coffey MJ, Katz T, Strachan R, Pang T, Needham B, Lui K, Ali F, Day AS, Appleton L, Moeeni V, Jaffe A, Ooi CY

Abstract
BACKGROUND: Fecal calprotectin may be used as a non-invasive method to assess the effect of novel therapies on the gut in cystic fibrosis (CF).
METHOD: Stools from CF patients and healthy controls (HC) (0-10years old) were prospectively collected for evaluation of temporal trends.
RESULTS: 130 CF samples (64 subjects) and 114 HC samples (101 subjects) were collected. Overall, fecal calprotectin levels were different in CF patients and HC from 0 to 10years (P=0.0002). Fecal calprotectin in CF was significantly lower than HC from 0 to 1years (P=0.03) and demonstrated an upward trajectory until 4years. From >4 to 10years calprotectin was consistently higher in CF patients compared with HC (P=0.007).
CONCLUSIONS: Fecal calprotectin levels in children with CF and HC were age-dependent and had distinct trajectories. Careful interpretation of calprotectin is required if used in drug trials for CF, particularly in children less than 4years old.

PMID: 28416415 [PubMed - as supplied by publisher]

Related Articles

Telemedicine is the way forward for the management of Cystic Fibrosis - the case in favour: The debate: Telemedicine is the future for CF care.

Paediatr Respir Rev. 2017 Mar 15;:

Authors: Ketchell RI

Abstract
Despite rapid changes in Information and Communication Technology, outpatient chronic disease management has changed very little in decades. However, the introduction of Telemedicine defined here as the use of remote patient-centred clinical services including the use of video and audio connections, telemonitoring and mobile applications provides us with an ideal opportunity to revolutionise care. Its appeal in cystic fibrosis (CF) care is clear offering better access to services, the opportunity of earlier intervention and improved monitoring and self management through virtual clinics and the use of real-time applications for adherence monitoring. It has the potential to reduce costs and has been shown to be effective in other chronic disease conditions. There is a lack of good quality data in CF and studies are needed to provide supportive evidence. Nonetheless, it would seem that telemedicine is the future of CF care.

PMID: 28416301 [PubMed - as supplied by publisher]