Notice NOT-MH-18-030 from the NIH Guide for Grants and Contracts

Notice NOT-MH-18-029 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-FD-18-021 from the NIH Guide for Grants and Contracts. Food and Drug Administration/ Center for Devices and Radiological (CDRH) is announcing its intention to accept and consider a single source application for the award of a cooperative agreement in fiscal year 2018 to Conference of Radiation Control Program Directors, Inc. (CRCPD) in support of coordination of Federal and State actions to assure radiation protection of the American public. The primary purpose of this cooperative agreement is to assist CRCPD members (State radiation control programs) in their efforts to protect the public, radiation workers and patients from unnecessary radiation exposure. Its goals will include: 1.Producing radiation protection solutions that meet community needs. 2.Assisting States with improving tools for radiation control. 3.Coordinate Federal, State and Tribal activities to achieve effective solutions to present and future radiation control problems. 4.Be expected to obtain the States cooperation and participation on committees and working groups established to deal with individual problems. 5.Plan and facilitate an annual meeting, and develop and offer educational activities to demonstrate mutually beneficial techniques, procedures, and systems relevant to the mission of assuring radiation protection. 6.Establish committees to address, evaluate, and offer solutions for a wide range of radiation health and protection issues. 7. Providing training in radiation control for CRCPD members.

Funding Opportunity RFA-FD-18-011 from the NIH Guide for Grants and Contracts. As part of FDA's Advancing Regulatory Science Initiative, the Office of the Chief Scientist supports innovation aimed at development of new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. This funding opportunity will provide support, depending on availability of FDA funding, for one or more of the following existing Centers of Excellence in Regulatory Science and Innovation (CERSIs): Yale University-Mayo Clinic, University of Maryland at College Park and Baltimore and Johns Hopkins University. The CERSI(s) will serve to advance the Agency's regulatory science goals predominantly through cutting-edge collaborative research with FDA; they may also provide training in regulatory science.

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

These pubmed results were generated on 2018/03/23

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.

The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment?

J Alzheimers Dis. 2018;62(3):1443-1466

Authors: Kehoe PG

Abstract
There is wide recognition of a complex association between midlife hypertension and cardiovascular disease and later development of Alzheimer's disease (AD) and cognitive impairment. While significant progress has been made in reducing rates of mortality and morbidity due to cardiovascular disease over the last thirty years, progress towards effective treatments for AD has been slower. Despite the known association between hypertension and dementia, research into each disease has largely been undertaken in parallel and independently. Yet over the last decade and a half, the emergence of converging findings from pre-clinical and clinical research has shown how the renin angiotensin system (RAS), which is very important in blood pressure regulation and cardiovascular disease, warrants careful consideration in the pathogenesis of AD. Numerous components of the RAS have now been found to be altered in AD such that the multifunctional and potent vasoconstrictor angiotensin II, and similarly acting angiotensin III, are greatly altered at the expense of other RAS signaling peptides considered to contribute to neuronal and cognitive function. Collectively these changes may contribute to many of the neuropathological hallmarks of AD, as well as observed progressive deficiencies in cognitive function, while also linking elements of a number of the proposed hypotheses for the cause of AD. This review discusses the emergence of the RAS and its likely importance in AD, not only because of the multiple facets of its involvement, but also perhaps fortuitously because of the ready availability of numerous RAS-acting drugs, that could be repurposed as interventions in AD.

PMID: 29562545 [PubMed - in process]

Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches.

J Alzheimers Dis. 2018 Mar 16;:

Authors: Clarke JR, Ribeiro FC, Frozza RL, De Felice FG, Lourenco MV

Abstract
Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.

PMID: 29562518 [PubMed - as supplied by publisher]

Heterogeneous Antimicrobial Susceptibility Characteristics in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients.

mSphere. 2018 Mar-Apr;3(2):

Authors: Qin X, Zhou C, Zerr DM, Adler A, Addetia A, Yuan S, Greninger AL

Abstract
Clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis (CF) are known to differ from those associated with non-CF hosts by colony morphology, drug susceptibility patterns, and genomic hypermutability. Pseudomonas aeruginosa isolates from CF patients have long been recognized for their overall reduced rate of antimicrobial susceptibility, but their intraclonal MIC heterogeneity has long been overlooked. Using two distinct cohorts of clinical strains (n = 224 from 56 CF patients, n = 130 from 68 non-CF patients) isolated in 2013, we demonstrated profound Etest MIC heterogeneity in CF P. aeruginosa isolates in comparison to non-CF P. aeruginosa isolates. On the basis of whole-genome sequencing of 19 CF P. aeruginosa isolates from 9 patients with heterogeneous MICs, the core genome phylogenetic tree confirmed the within-patient CF P. aeruginosa clonal lineage along with considerable coding sequence variability. No extrachromosomal DNA elements or previously characterized antibiotic resistance mutations could account for the wide divergence in antimicrobial MICs between P. aeruginosa coisolates, though many heterogeneous mutations in efflux and porin genes and their regulators were present. A unique OprD sequence was conserved among the majority of isolates of CF P. aeruginosa analyzed, suggesting a pseudomonal response to selective pressure that is common to the isolates. Genomic sequence data also suggested that CF pseudomonal hypermutability was not entirely due to mutations in mutL, mutS, and uvr. We conclude that the net effect of hundreds of adaptive mutations, both shared between clonally related isolate pairs and unshared, accounts for their highly heterogeneous MIC variances. We hypothesize that this heterogeneity is indicative of the pseudomonal syntrophic-like lifestyle under conditions of being "locked" inside a host focal airway environment for prolonged periods. IMPORTANCE Patients with cystic fibrosis endure "chronic focal infections" with a variety of microorganisms. One microorganism, Pseudomonas aeruginosa, adapts to the host and develops resistance to a wide range of antimicrobials. Interestingly, as the infection progresses, multiple isogenic strains of P. aeruginosa emerge and coexist within the airways of these patients. Despite a common parental origin, the multiple strains of P. aeruginosa develop vastly different susceptibility patterns to actively used antimicrobial agents-a phenomenon we define as "heterogeneous MICs." By sequencing pairs of P. aeruginosa isolates displaying heterogeneous MICs, we observed widespread isogenic gene lesions in drug transporters, DNA mismatch repair machinery, and many other structural or cellular functions. Coupled with the heterogeneous MICs, these genetic lesions demonstrated a symbiotic response to host selection and suggested evolution of a multicellular syntrophic bacterial lifestyle. Current laboratory standard interpretive criteria do not address the emergence of heterogeneous growth and susceptibilities in vitro with treatment implications.

PMID: 29564400 [PubMed]

Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients.

Open Forum Infect Dis. 2018 Mar;5(3):ofy034

Authors: Caimmi D, Martocq N, Trioleyre D, Guinet C, Godreuil S, Daniel T, Chiron R

Abstract
Mycobacterium abscessus is difficult to eradicate. At the Montpellier CF Center, we prescribed liposomal amikacin for inhalation to 5 patients with M abscessus infection. The 3 patients who completed the treatment did not have any respiratory exacerbation, showed negative cultures for M abscessus in their sputum, and stabilized their spirometric functions.

PMID: 29564361 [PubMed]

Antimicrobial resistance and putative virulence genes of Pseudomonas aeruginosa isolates from patients with respiratory tract infection.

Germs. 2018 Mar;8(1):31-40

Authors: Al Dawodeyah HY, Obeidat N, Abu-Qatouseh LF, Shehabi AA

Abstract
Introduction: Pseudomonas aeruginosa is a common agent causing community acquired and nosocomial respiratory tract infections, with particularly life-threatening manifestations in patients who are immunocompromised of who have cystic fibrosis. This study investigated the occurrence of extended-spectrum β-lactamases (ESBLs) and metallo β-lactamase (MBL) in association with important putative virulence genes and genotypes variation among P. aeruginosa isolates from respiratory tract infection of Jordanian patients.
Methods: Over a period of 8-month, a total of 284 respiratory tract samples were obtained from patients diagnosed with respiratory tract infection while attending the Pulmonary Clinic/Intensive Care Unit, Jordan University Hospital (JUH). At the time of sampling most were inpatients (86.9%). Samples were cultured specifically for P. aeruginosa.
Results: A total of 61/284 (21.5%) P. aeruginosa isolates were recovered from respiratory samples of patients. The percentage of MDR P. aeruginosa isolates was 52.5%, and all isolates were susceptible to colistin with lower rates of susceptibility to other tested antibiotics. Positive genes of blaCTX-M, blaVEB, blaTEM, blaGES and blaSHV were detected in 68.9%, 18.9%, 18.9%, 15.6% and 12.5% of isolates, respectively. Genotyping revealed no significant genetic relationship among MDR P. aeruginosa isolates from hospitalized patients as judged by the constructed dendrogram and the presence of 14 genotypic groups. The percentages of the virulence genes algD, lasB, toxA, exoS, and exoU among P. aeruginosa isolates were 98%, 98%, 80%, 33% and 33%, respectively, and 87% of isolates produced pyocyanin.
Conclusion: The present study demonstrates high occurrence of MDR P. aeruginosa isolates carrying blaCTX-M genes. No specific associations were found between antibiotic resistance, virulence genes and genotypes among MDR isolates.

PMID: 29564246 [PubMed]

Subtyping of polyposis nasi: phenotypes, endotypes and comorbidities.

Allergo J Int. 2018;27(2):56-65

Authors: Koennecke M, Klimek L, Mullol J, Gevaert P, Wollenberg B

Abstract
Background: Chronic rhinosinusitis (CRS) is a heterogeneous, multifactorial inflammatory disease of the nasal and paranasal mucosa. It has not been possible to date to develop an internationally standardized, uniform classification for this disorder. A phenotype classification according to CRS with (CRSwNP) and without polyposis (CRSsNP) is usually made. However, a large number of studies have shown that there are also different endotypes of CRS within these phenotypes, with different pathophysiologies of chronic inflammation of the nasal mucosa. This review describes the central immunological processes in nasal polyps, as well as the impact of related diseases on the inflammatory profile of nasal polyps.
Materials and methods: The current knowledge on the immunological and molecular processes of CRS, in particular CRSwNP and its classification into specific endotypes, was put together by means of a structured literature search in Medline, PubMed, the national and international guideline registers, and the Cochrane Library.
Results: Based on the current literature, the different immunological processes in CRS and nasal polyps were elaborated and a graphical representation in the form of an immunological network developed. In addition, different inflammatory profiles can be found in CRSwNP depending on related diseases, such as bronchial asthma, cystic fibrosis (CF), or NASID-Exacerbated Respiratory Disease (N‑ERD).
Conclusion: The identification of different endotypes of CRSwNP may help to improve diagnostics and develop novel individual treatment approaches in CRSwNP.

PMID: 29564208 [PubMed]

Estimating the Burden of Serious Fungal Infections in Uruguay.

J Fungi (Basel). 2018 Mar 18;4(1):

Authors: Macedo-Viñas M, Denning DW

Abstract
We aimed to estimate for the first time the burden of fungal infections in Uruguay. Data on population characteristics and underlying conditions were extracted from the National Statistics Institute, the World Bank, national registries, and published articles. When no data existed, risk populations were used to estimate frequencies extrapolating from the literature. Population structure (inhabitants): total 3,444,006; 73% adults; 35% women younger than 50 years. Size of populations at risk (total cases per year): HIV infected 12,000; acute myeloid leukemia 126; hematopoietic stem cell transplantation 30; solid organ transplants 134; COPD 272,006; asthma in adults 223,431; cystic fibrosis in adults 48; tuberculosis 613; lung cancer 1400. Annual incidence estimations per 100,000: invasive aspergillosis, 22.4; candidemia, 16.4; Candida peritonitis, 3.7; Pneumocystis jirovecii pneumonia, 1.62; cryptococcosis, 0.75; severe asthma with fungal sensitization, 217; allergic bronchopulmonary aspergillosis, 165; recurrent Candida vaginitis, 6323; oral candidiasis, 74.5; and esophageal candidiasis, 25.7. Although some under and overestimations could have been made, we expect that at least 127,525 people suffer from serious fungal infections each year. Sporothrichosis, histoplasmosis, paracoccidioidomycosis, and dermatophytosis are known to be frequent but no data are available to make accurate estimations. Given the magnitude of the burden of fungal infections in Uruguay, efforts should be made to improve surveillance, strengthen laboratory diagnosis, and warrant access to first line antifungals.

PMID: 29562641 [PubMed]

Formyl peptide receptor 2 mediated chemotherapeutics drug resistance in colon cancer cells. Point of view from pharmacogenetics field.

Eur Rev Med Pharmacol Sci. 2018 Mar;22(5):1178-1179

Authors: Marotta G, Muto T, Benincasa G, De Monaco A

PMID: 29565471 [PubMed - in process]

Drug-Induced Skin Adverse Reactions: The Role of Pharmacogenomics in Their Prevention.

Mol Diagn Ther. 2018 Mar 21;:

Authors: Gerogianni K, Tsezou A, Dimas K

Abstract
Adverse drug reactions (ADRs) affect many patients and remain a major public health problem, as they are a common cause of morbidity and mortality. It is estimated that ADRs are responsible for about 6% of hospital admissions and about 9% of hospitalization costs. Skin is the organ that is most frequently involved in ADRs. Drug-induced skin injuries vary from mild maculopapular eruptions (MPE) to severe cutaneous adverse reactions (SCARs) that are potentially life threatening. Genetic factors have been suggested to contribute to these SCARs, and most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes. Common drugs associated with SCARs connected with strong genetic risk factors include antiepileptic drugs (AEDs), allopurinol, abacavir, nevirapine, sulfonamides, dapsone, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesic drugs. However, genetic associations vary between different ethnic populations. Differences may in part be explained by the different prevalence of HLA (human leukocyte antigen) alleles among ethnic groups. In this review, we present and discuss the recent advances in genetic associations with ADRs in the skin. Many of these ADRs are now preventable with pharmacogenetic screening.

PMID: 29564734 [PubMed - as supplied by publisher]

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment.

Pharmgenomics Pers Med. 2018;11:23-33

Authors: Chen L, Prasad GVR

Abstract
Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between CYP3A5 genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. CYP3A5 genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. CYP3A5 genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of CYP3A5 genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.

PMID: 29563827 [PubMed]

Related Articles

Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis.

Toxicol In Vitro. 2017 Sep;43:87-91

Authors: Celestino Pinto L, de Fátima Aquino Moreira-Nunes C, Soares BM, Burbano RMR, de Lemos JAR, Montenegro RC

Abstract
The present study aimed to investigate whether MBZ down-regulates drug transporter expression (ABCB1, ABCC1, SLC47A1). mRNA expression level of ABCB1, ABCC1 and SLC47A1 was evaluated by qPCR and protein expression levels MDR-1 was performed by western blotting in malignant ascites cells (AGP-01) treated with MBZ for 24h. The mRNA expression level of ABCB1 and ABCC1 significantly decreased at a 1.0μM of MBZ compared to negative control, while SLC47A1 extremely decreased at all tested concentrations of MBZ. Protein expression levels MDR-1 significantly decreased at a 1.0μM of MBZ compared to negative control. Therefore, our results showed MBZ may play an important role in inhibiting MDR gene expression in malignant ascites cells.

PMID: 28606429 [PubMed - indexed for MEDLINE]

Related Articles

High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients.

Oncotarget. 2017 May 23;8(21):34387-34397

Authors: Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC

Abstract
Transforming growth factor beta (TGF-β) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-β1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-β1 expression. Eligible studies were retrieved from several databases, and effects (hazard ratios (HRs) with 95% confidence intervals (CIs)) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), metastasis-free survival (MFS), and progression-free survival (PFS) were pooled to assess the prognostic ability of TGF-β1 expression in HCC patients. Twelve qualified articles and our TCGA data comprising 2,021 HCC patients were incorporated. In the TCGA analysis, HCC patients with higher TGF-β1 expression presented a shorter OS than those with lower TGF-β1 expression (HR = 1.42, p < 0.05). In the meta-analysis, univariate analyses showed that HCC patients with higher TGF-β1 expression had a shorter OS (pooling HR = 1.71, p < 0.01) and DFS/RFS/MFS/PFS (pooling HR = 1.60, p < 0.01) than those with lower TGF-β1 expression. In conclusion, our results suggested that high TGF-β1 expression promotes a poor prognosis in HCC patients.

PMID: 28415739 [PubMed - indexed for MEDLINE]

Evaluation of surrogate measures of pulmonary function derived from electrical impedance tomography data in children with cystic fibrosis.

Physiol Meas. 2018 Mar 22;:

Authors: Muller PA, Mueller JL, Mellenthin M, Murthy R, Capps M, Wagner B, Alsaker M, Deterding R, Sagel SD, Hoppe J

Abstract
BACKGROUND: Lung function monitoring by spiromety plays a critical role in the clinical care of pediatric cystic fibrosis (CF) patients, but many young children are unable to perform spirometry, and the outputs are often normal even in the presence of lung disease. Measures derived from electrical impedance tomography (EIT) images were studied for their utility as potential surrogates for spirometry in CF patients and to assess response to intravenous antibiotic treatment for acute pulmonary exacerbations (PEx) in a subset of patients. &#13; Methods: EIT data were collected on 35 subjects (21 with CF, 14 healthy controls, 8 CF patients pre- and post-treatment for an acute PEx) ages 2 to 20 years during tidal breathing and also concurrently with spirometry on subjects over age 8. EIT-derived measures of FEV1, FVC, and FEV1/FVC were computed globally and regionally from dynamic EIT images. &#13; Results: Global EIT-derived FEV1/FVC showed good correlation with spirometry FEV1/FVC values (r=0.54, p=0.01), and were able to distinguish between the groups (p=0.01). Lung heterogeneity was assessed through the spatial coefficient of variation (CV) of EIT difference images between key time points, and the CV's for EIT-derived FEV1 and FVC showed significant correlation with the CV for tidal breathing (r=0.47, p=0.01 and r=0.50, p=0.01, respectively). Global EIT-derived FEV1/FVC was better able to distinguish between groups than spirometry FEV1 (F-values 776.5 and 146.3, respectively, p &lt; 0.01.) The same held true for the CV's for EIT-dervived FEV1, FVC, and Tidal Breathing (F-values 215.93, 193.89, 204.57, respectively, p &lt; 0.01.).

PMID: 29565263 [PubMed - as supplied by publisher]

Hepatotoxicity after paracetamol overdose in a patient with cystic fibrosis despite early acetylcysteine and utility of microRNA to predict hepatotoxicity.

Clin Toxicol (Phila). 2018 Mar 22;:1-3

Authors: Wong A, Cheung B, Nejad C, Gantier M, Graudins A

Abstract
CASE DETAILS: A 19-year-old girl presented to the emergency department following overdose of 10 g of paracetamol on a background history of cystic fibrosis. Paracetamol concentration was below the nomogram line, but was treated with acetylcysteine seven hours post-overdose given her symptomatology. Nineteen hours following her overdose she developed hepatotoxicity, despite early initiation of acetylcysteine. She was discharged well six days post-ingestion. On presentation, delta miRNA-122-miR483 was 20 times that of control patients, however, alanine aminotransferase was normal.
DISCUSSION: Patients with cystic fibrosis are more likely to have glutathione deficiency, and greater susceptibility to liver injury. Delta miRNA may be a better detector of early liver injury than hepatic aminotransferases. Empiric treatment with acetylcysteine and serial biochemical reassessment in this setting should be considered.

PMID: 29564929 [PubMed - as supplied by publisher]