Funding Opportunity PA-18-660 from the NIH Guide for Grants and Contracts. The goal of this FOA is to develop new hypotheses and common experimental framework(s) between human - animal model studies to better understand the genetic, genomic, and epigenetic factors contributing to and underlying biological bases for the development of tolerance and the progression to alcohol dependence.

Funding Opportunity PAR-18-659 from the NIH Guide for Grants and Contracts. The intent of this FOA is two-fold: (1) develop new hypotheses about key factors and pathways in sensitivity and tolerance to alcohol, and (2) develop a common framework of mechanisms underlying the development of tolerance and the progression to alcohol dependence. These objectives will be accomplished with a Phased Innovation (R21/R33) mechanism, in which secondary data analysis or pilot studies can occur during the R21 phase, and research testing the hypotheses can be expanded in the R33 phase.

Funding Opportunity RFA-CA-18-011 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits Small Business Innovation Research (SBIR) applications from small business concerns (SBCs) that seek additional funding to support the next stage of development for projects that were previously funded under SBIR or STTR Phase II awards from any Federal agency. Projects proposed in response to this FOA must be applicable to one of the following areas: (1) cancer therapeutics; (2) cancer imaging technologies, interventional devices, and/or in vivo diagnostics; or (3) in vitro and ex vivo cancer diagnostics and prognostics. The purpose of this FOA is to facilitate the transition of SBIR or STTR Phase II projects to the commercialization stage. This FOA is expected to promote partnerships between Federally-funded SBIR or STTR Phase II awardees and third-party investors and/or strategic partners to facilitate and accelerate the capital-intensive steps that are required to commercialize new products and services. Applicants must submit a Commercialization Plan, which should include details on any independent third-party investor funding that has already been secured or is anticipated during the Phase IIB Bridge Award project period. It is expected that the level of this independent third-party funding will be equal to or greater than the NCI funds being requested throughout the Phase IIB Bridge Award project period. Proposed projects may address preclinical and/or clinical stages of technology development. Clinical trials may be proposed as appropriate but are not required

Funding Opportunity RFA-AG-18-031 from the NIH Guide for Grants and Contracts. This RFA invites applications for planning awards to develop and finalize protocols for well-powered cognitive training intervention trials to remediate or prevent age-related cognitive decline as well as possibly prevent or delay the onset of mild cognitive impairment and dementia. Planning activities may include the collection of pilot data and the refinement of cognitive training protocols consistent with Stage I of the NIH Stage Model. Trial designs must justify the means used to assess cognition and to explore the underlying mechanisms of change. Such methods as structural and functional neuroimaging with biomarkers justified by an underlying model of change, CSF fluids, and blood biomarkers are appropriate candidate tools.

Funding Opportunity PAR-18-662 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications for investigator-initiated multi-site clinical trials (e.g. efficacy, effectiveness or pragmatic trials) to study the effects of mind and body interventions in NCCIH designated areas of high research priority. Clinical Coordinating Centers should develop and implement the proposed multi-site clinical trial. The objective of a Clinical Coordinating Center application is to present the scientific rationale and a comprehensive scientific and operational plan for the clinical trial. Clinical Coordinating Center applications are expected to describe plans for project management, participant recruitment and retention strategies, performance milestones , scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism . In addition, an accompanying Data Coordinating Center application, submitted under PAR-18-116 (https ://grants.nih.gov/grants/guide/pa-files/PAR-18-116.html) proposing a data analysis and data management plan for the clinical project is required. Both a Clinical Coordinating Center application and a corresponding Data Coordinating Center (DCC) application need to be submitted simultaneously for consideration by NCCIH. For additional information about the mission, strategic vision, and research priorities of the NCCIH, applicants are encouraged to consult the NCCIH website : (https://nccih.nih.gov/about/plans (https://nccih.nih.gov/about/plans )). Applicants are encouraged to contact the appropriate the Scientific/Research contact for the area of science for which they are planning to develop an application prior to submitting to this FOA.

Funding Opportunity PAR-18-663 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA), utilizing the U24 grant funding mechanism, encourages applications for a collaborating Data Coordinating Center (DCC) application that accompanies an investigator-initiated multi-site clinical trial (Phase Ill and beyond) application submitted under PAR-18-117 (https://grants.nih.gov/grants/guide/pa-files/PAR-18- 117.html}. The DCC application must be specific to the collaborating Clinical Coordinating Center (CCC) application. The objective of the DCC application is to propose a comprehensive plan that provides overall project coordination, and administrative, data management, and biostatistical support for the proposed clinical trial. Both a DCC application and a corresponding CCC application need to be submitted simultaneously for consideration by NCCIH. Trials for which this FOA applies must be relevant to the research mission of the NCCIH and considered a high priority by the Center. For additional information about the mission, strategic vision, and research priorities of the NCCIH, applicants are encouraged to consult the NCCIH website: (http://www.nccih.nih.gov (http://www.nccih.nih.gov)). Applicants are encouraged to contact the appropriate the Scientific/Research contact for the area of science for which they are planning to develop an application prior to submitting to this FOA.

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Funding Opportunity PAR-18-661 from the NIH Guide for Grants and Contracts. The purpose of the FOA is to support the large scale molecular platform analysis of brain tissue, human biofluid or human induced pluripotent stem cell resources for the identification of targets and pathways associated with Alzheimer's Disease Related Dementias (ADRDs) pathophysiology.

Funding Opportunity RFA-HD-19-004 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite SBIR applications to support and facilitate the development of new and/or improved contraceptive products for men and women.

Related Articles

[Patient with homozygous sickle cell disease and free flap surgery: Ensuring the success of the procedure].

Ann Chir Plast Esthet. 2017 Apr;62(2):171-175

Authors: Deneuve S, Maire L, Bachelot V, Dammacco MA, Zrounba P, Delay E

Abstract
Sickle cell anaemia is rare in France but frequent in Africa, leading to rigid, sickle-like shape red blood cells which bind together blocking microcirculation under certain circumstances. The vaso-occlusive crisis is the most frequent clinical manifestation especially in case of homozygous disease. Sickle cells disease is therefore usually considerated as a contraindication to microsurgery, however sometimes, a free flap procedure is mandatory. We here report the case of a 47-year-old man suffering with homozygous sickle cell anaemia and needing an antebrachial free flap procedure for a tongue reconstruction. The postoperative course was unremarkable apart from a delayed healing which is common in this particular localization. A review of the litterature allows to list the precautions to be taken to ensure a microsurgical procedure with this medical background. The preoperative examination has to assess usual sickle cell disease comorbidities such as kidney failure, heart failure or pulmonary hypertension. All the events leading to either low output syndrome, hypoxia, hypothermia, or a stress caused by uncontrolled pain should be avoided per- and postoperatively. With an optimum medical care, microsurgery is possible even in patients suffering with sickle cells anaemia. This case is rare in France but will become frequent in Africa with the improvement of the healthcare system, allowing to give all patients the best medical care.

PMID: 27692921 [PubMed - indexed for MEDLINE]

Related Articles

The attitudes of medical students towards rare diseases: A cross-sectional study.

Vojnosanit Pregl. 2016 Aug;73(8):703-13

Authors: Medić B, Divac N, Stopić N, Savić-Vujović K, Glišić A, Cerovac N, Stojanović R, Srebro D, Prostran M

Abstract
Background/Aim: Rare diseases are chronic, degenerative and may lead to permanent disability. We aimed to assess knowledge and attitudes of the 3rd and 6th year medical students towards the treatment of rare diseases in Serbia. Methods. In this cross-sectional study, two samples of students were questioned for a survey: 350/446 (78.48%) students of the 3rd year, and 242/517 (46.81%) students of the 6th year.
Methods: In this cross-sectional study, two samples of students were questioned for a survey: 350/446 (78.48%) students of the 3rd year, and 242/517 (46.81%) students of the 6th year.
Results: Sixth year students estimated that they were more informed on the issue analyzed than the 3rd year students (median value of 4 and 3, interquartile range of 3-5, and 1-4, respectively; p < 0.05). However, a significant percentage of participants estimated incorrectly the prevalence of rare diseases according to the European Union standards (3rd year - 42.68%, 6th year - 49.55%). Core curriculum subjects were the main source of information on rare diseases (3rd year - 63.14%; 6th year - 92.14%). Our participants agreed that the most important problems are the following: high drug prices, difficult access to drugs and lack of public information. Students found, without any differences, that community access to effective drugs for rare disease should be improved (median value - 10, interquartile range 8-10 in both groups, p < 0.05). In order to improve pharmacotherapy of rare diseases in Serbia, the participants suggested establishment of a National Plan for Rare Diseases, approval of more appropriate drugs, simplified access to appropriate medicines, and more rapid diagnostics.
Conclusion: It is necessary to improve the knowledge and attitudes of medical students towards pharmacotherapy of rare diseases. [Projekat Ministarstva nauke Republike Srbije, br. 175023]

PMID: 29328568 [PubMed - indexed for MEDLINE]

Related Articles

The canonical semantic network supports residual language function in chronic post-stroke aphasia.

Hum Brain Mapp. 2017 Mar;38(3):1636-1658

Authors: Griffis JC, Nenert R, Allendorfer JB, Vannest J, Holland S, Dietz A, Szaflarski JP

Abstract
Current theories of language recovery after stroke are limited by a reliance on small studies. Here, we aimed to test predictions of current theory and resolve inconsistencies regarding right hemispheric contributions to long-term recovery. We first defined the canonical semantic network in 43 healthy controls. Then, in a group of 43 patients with chronic post-stroke aphasia, we tested whether activity in this network predicted performance on measures of semantic comprehension, naming, and fluency while controlling for lesion volume effects. Canonical network activation accounted for 22%-33% of the variance in language test scores. Whole-brain analyses corroborated these findings, and revealed a core set of regions showing positive relationships to all language measures. We next evaluated the relationship between activation magnitudes in left and right hemispheric portions of the network, and characterized how right hemispheric activation related to the extent of left hemispheric damage. Activation magnitudes in each hemispheric network were strongly correlated, but four right frontal regions showed heightened activity in patients with large lesions. Activity in two of these regions (inferior frontal gyrus pars opercularis and supplementary motor area) was associated with better language abilities in patients with larger lesions, but poorer language abilities in patients with smaller lesions. Our results indicate that bilateral language networks support language processing after stroke, and that right hemispheric activations related to extensive left hemispheric damage occur outside of the canonical semantic network and differentially relate to behavior depending on the extent of left hemispheric damage. Hum Brain Mapp 38:1636-1658, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 27981674 [PubMed - indexed for MEDLINE]

Posttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicing.

Drug Metab Dispos. 2018 Feb 09;:

Authors: Labriet A, Allain EP, Rouleau M, Audet-Delage Y, Villeneuve L, Guillemette C

Abstract
The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines such as tobacco carcinogens and several anti-depressants and anti-psychotics. We hypothesized that alternative splicing (AS) constitutes a mean to regulate steady state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. Highest expression was in the liver, where ten AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C-termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5 fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they co-localized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40-70%; P<0.01), in a cell context-specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodelling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme activity.

PMID: 29438977 [PubMed - as supplied by publisher]

Penetration of cefotaxime into cerebrospinal fluid in neonates and young infants.

Antimicrob Agents Chemother. 2018 Feb 05;:

Authors: Chen XK, Shi HY, Leroux S, Xu HY, Zhou Y, Zheng Y, Huang X, Li Y, Jacqz-Aigrain E, Zhao W

Abstract
Objective: Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study is to evaluate the penetration of cefotaxime into CSF in neonates and young infants.Methods: Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy and concentrations were quantified by HPLC-MS/MS. The analysis was performed using NONMEM and R software.Results: Thirty neonates and young infants (PMA range: 25.4-47.4 weeks) were included. A total of 67 plasma and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter, and from 0.39 to 25.38 mg/liter, respectively. The median ratio of CSF to plasma concentrations was 0.28 (range 0.06-0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg TID would reach the pharmacodynamic target (70% fT>MIC) using the standard EUCAST MIC susceptibility breakpoint of 2 mg/liter and 4 mg/liter, respectively.Conclusion: The penatration of cefotaxime into CSF was evaluted in neonates and young infants using an opportunistic sampling appoarch. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MIC<2 mg/liter. The individual dosage adaptation was required for more resistant bacterial strains such as Staphylococcus aureus.

PMID: 29437625 [PubMed - as supplied by publisher]

Evaluation of prescriber responses to pharmacogenomics clinical decision support for thiopurine S-methyltransferase testing.

Am J Health Syst Pharm. 2018 Feb 15;75(4):191-198

Authors: Ubanyionwu S, Formea CM, Anderson B, Wix K, Dierkhising R, Caraballo PJ

Abstract
PURPOSE: Results of a study of prescribers' responses to a pharmacogenomics-based clinical decision support (CDS) alert designed to prompt thiopurine S-methyltransferase (TPMT) status testing are reported.
METHODS: A single-center, retrospective, chart review-based study was conducted to evaluate prescriber compliance with a pretest CDS alert that warned of potential thiopurine drug toxicity resulting from deficient TPMT activity due to TPMT gene polymorphism. The CDS alert was triggered when prescribers ordered thiopurine drugs for patients whose records did not indicate TPMT status or when historical thiopurine use was documented in the electronic health record. The alert pop-up also provided a link to online educational resources to guide thiopurine dosing calculations.
RESULTS: During the 9-month study period, 500 CDS alerts were generated: in 101 cases (20%), TPMT phenotyping or TPMT genotyping was ordered; in 399 cases (80%), testing was not ordered. Multivariable regression analysis indicated that documentation of historical thiopurine use was the only independent predictor of test ordering. Among the 99 patients tested subsequent to CDS alerts, 70 (71%) had normal TPMT activity, 29 (29%) had intermediate activity, and none had deficient activity. The online resources provided thiopurine dosing recommendations applicable to 24 patients, but only 3 were prescribed guideline-supported doses after CDS alerts.
CONCLUSION: The pretest CDS rule resulted in a large proportion of neglected alerts due to poor alerting accuracy and consequent alert fatigue. Prescriber usage of online thiopurine dosing resources was low.

PMID: 29436466 [PubMed - in process]

Related Articles

Misleading Guidance From Pharmacogenomic Testing.

Am J Psychiatry. 2017 Oct 01;174(10):922-924

Authors: Rahman T, Ash DM, Lauriello J, Rawlani R

PMID: 28965468 [PubMed - indexed for MEDLINE]

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine.

J Innate Immun. 2018 Feb 13;:

Authors: Hartl D, Tirouvanziam R, Laval J, Greene CM, Habiel D, Sharma L, Yildirim AÖ, Dela Cruz CS, Hogaboam CM

Abstract
The respiratory tract is faced daily with 10,000 L of inhaled air. While the majority of air contains harmless environmental components, the pulmonary immune system also has to cope with harmful microbial or sterile threats and react rapidly to protect the host at this intimate barrier zone. The airways are endowed with a broad armamentarium of cellular and humoral host defense mechanisms, most of which belong to the innate arm of the immune system. The complex interplay between resident and infiltrating immune cells and secreted innate immune proteins shapes the outcome of host-pathogen, host-allergen, and host-particle interactions within the mucosal airway compartment. Here, we summarize and discuss recent findings on pulmonary innate immunity and highlight key pathways relevant for biomarker and therapeutic targeting strategies for acute and chronic diseases of the respiratory tract.

PMID: 29439264 [PubMed - as supplied by publisher]

Liver disease in patients with cystic fibrosis.

Curr Opin Gastroenterol. 2018 Feb 12;:

Authors: Kamal N, Surana P, Koh C

Abstract
PURPOSE OF REVIEW: The aim of this study was to provide an overview of the current understanding of the pathophysiology, diagnosis and management of cystic fibrosis-liver disease (CFLD).
RECENT FINDINGS: CFLD has a variety of manifestations. Previously, it was thought that patients progressed from mild cholestatic disease to cirrhosis to decompensated cirrhosis with portal hypertension. Newer evidence suggests that some patients may develop cirrhosis while others develop noncirrhotic portal hypertension. Advances in our understanding of the pathophysiology of disease necessitate modifications to the current diagnostic criteria. Both fibroscan and noninvasive biomarkers can be used to identify patients with cirrhosis and portal hypertension. Ursodeoxycholic acid remains the mainstay of therapy despite a paucity of rigorous studies supporting its use. Novel therapeutic agents such as CF transmembrane conductance regulator (CFTR) modulators and potentiators are encouraging but need to be evaluated specifically in CFLD.
SUMMARY: A better understanding of the pathophysiology of disease is critical to developing more disease-specific diagnostics and therapeutics.

PMID: 29438119 [PubMed - as supplied by publisher]

Role of iodide metabolism in physiology and cancer.

Endocr Relat Cancer. 2018 Feb 01;:

Authors: De la Vieja A, Santisteban P

Abstract
Iodide (I-) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I- is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I- recycling. New research supports the exciting idea that I- participates as a protective antioxidant and can be oxidised to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I- in biological systems, before the appearance of TH in evolution. I- per se participates in its own regulation and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I- transporters are associated with tumor development in a cancer-type dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I-, has made NIS a preferred target-specific theranostic agent.

PMID: 29437784 [PubMed - as supplied by publisher]

Islet Interleukin-1β Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to β-Cell Failure.

Diabetes Care. 2018 Feb 01;:

Authors: Hull RL, Gibson RL, McNamara S, Deutsch GH, Fligner CL, Frevert CW, Ramsey BW, Sanda S

Abstract
OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes.
RESEARCH DESIGN AND METHODS: A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) (n = 18) and CF without diabetes (CF-no DM) (n = 17). Two cohorts of control non-CF subjects were identified, each matched to CFRD and CF-no DM subjects for age, sex, and BMI (non-CF older, n = 20, and non-CF younger, n = 20), respectively. Immunohistochemistry was performed to assess IL-1β and islet hormone (insulin, glucagon, somatostatin, and pancreatic polypeptide) immunoreactivity; histochemistry was performed to quantify amyloid deposition.
RESULTS: Islet IL-1β immunoreactivity was substantially increased in both CFRD and CF-no DM subjects compared with non-CF subjects and was common in young subjects with CF (≤10 years of age). In contrast, islet amyloid deposition was increased only in CFRD subjects. We also observe abnormal islet hormone immunoreactivity, characterized by increased glucagon immunoreactivity, in CF-no DM and CFRD subjects compared with non-CF subjects.
CONCLUSIONS: These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD.

PMID: 29437698 [PubMed - as supplied by publisher]