Funding Opportunity PAR-18-878 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages R01 grant applications that propose to develop and implement late stage (Phase II/III, III) clinical trials of promising pharmacological and non-pharmacological interventions in individuals with age-related cognitive decline and across the Alzheimer's disease (AD) spectrum from pre-symptomatic to more severe stages of disease.

Funding Opportunity PAR-18-877 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications that propose to develop and implement early stage (Phase I or II) clinical trials of promising pharmacological and non-pharmacological interventions in individuals with age-related cognitive decline and in individuals with Alzheimer's disease (AD) across the spectrum from pre-symptomatic to more severe stages of disease, as well as to stimulate studies to enhance trial design and methods.

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

These pubmed results were generated on 2018/07/26

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.

Related Articles

Physician-Reported Benefits and Barriers to Clinical Implementation of Genomic Medicine: A Multi-Site IGNITE-Network Survey.

J Pers Med. 2018 Jul 24;8(3):

Authors: Owusu Obeng A, Fei K, Levy KD, Elsey AR, Pollin TI, Ramirez AH, Weitzel KW, Horowitz CR

Abstract
Genetic medicine is one of the key components of personalized medicine, but adoption in clinical practice is still limited. To understand potential barriers and provider attitudes, we surveyed 285 physicians from five Implementing GeNomics In pracTicE (IGNITE) sites about their perceptions as to the clinical utility of genetic data as well as their preparedness to integrate it into practice. These responses were also analyzed in comparison to the type of study occurring at the physicians' institution (pharmacogenetics versus disease genetics). The majority believed that genetic testing is clinically useful; however, only a third believed that they had obtained adequate training to care for genetically "high-risk" patients. Physicians involved in pharmacogenetics initiatives were more favorable towards genetic testing applications; they found it to be clinically useful and felt more prepared and confident in their abilities to adopt it into their practice in comparison to those participating in disease genetics initiatives. These results suggest that investigators should explore which attributes of clinical pharmacogenetics (such as the use of simplified genetics-guided recommendations) can be implemented to improve attitudes and preparedness to implement disease genetics in care. Most physicians felt unprepared to use genetic information in their practice; accordingly, major steps should be taken to develop effective clinical tools and training strategies for physicians.

PMID: 30042363 [PubMed]

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MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections.

Front Microbiol. 2018;9:1547

Authors: Li W, Yazidi A, Pandya AN, Hegde P, Tong W, Calado Nogueira de Moura V, North EJ, Sygusch J, Jackson M

Abstract
Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.

PMID: 30042757 [PubMed]

Related Articles

Antidiarrheal Action of Bacillus subtilis CU1 CNCM I-2745 and Lactobacillus plantarum CNCM I-4547 in Mice.

Front Microbiol. 2018;9:1537

Authors: Urdaci MC, Lefevre M, Lafforgue G, Cartier C, Rodriguez B, Fioramonti J

Abstract
Preventive actions of probiotics as antidiarrheal agents are well documented, but their mechanisms are poorly understood. Two selected probiotics, Bacillus subtilis CU1 and Lactobacillus plantarum CNCM I-4547, were tested in mouse experimental models of diarrhea and the possible mechanisms of action were investigated. Diarrhea was induced in mice by oral castor oil administration or by i.v. injection of lipopolysaccharide (LPS) of Salmonella enteritis. The antidiarrheal drug loperamide was used as control. Fecal water excretion was quantified for 2 h and paracellular permeability and electrical parameters of the colon were assessed in Ussing chambers. The expression of colonic exchangers or channels and of Toll-like receptor 4 (TLR4) was assessed by immunohistochemistry. Prophylactic treatment with B. subtilis CU1 or with L. plantarum CNCM I-4547 reduced LPS-induced diarrhea. The reduction of water excretion was in the same range as those induced by loperamide. In the castor oil model, this effect was only observed with B. subtilis CU1. The two probiotic treatments abolished the increase in paracellular permeability induced by LPS, but not by castor oil. However, only L. plantarum CNCM I-4547 treatment decreased the colonic expression of TLR-4. After B. subtilis CU1, colonic expression of cystic fibrosis transmembrane conductance regulator (CFTR) was reduced and that of Na+/H+ exchanger 3 (NHE3) increased. B. subtilis CU1 may increase the capacity of the colon to absorb excess of water in diarrheic conditions by acting on CFTR and NHE3 expression. The two probiotics strains showed an impact on diarrhea through limitation of water excretion that may involve paracellular permeability or electrolyte transport for L. plantarum CNCM I-4547 and B. subtilis CU1 respectively.

PMID: 30042756 [PubMed]

Notice NOT-AI-18-044 from the NIH Guide for Grants and Contracts

Related Articles

Drug discovery for the treatment of substance use disorders: novel targets, repurposing, and the need for new paradigms.

Curr Opin Pharmacol. 2017 08;35:120-124

Authors: Chiamulera C, Padovani L, Corsi M

Abstract
Drug addiction treatment medications available nowadays are limited in both efficacy and number. The increased understanding of drug addiction circuitries leads the scientific community to look for better molecules and targets for detoxification and relapse prevention. This review focus on known targets (e.g., metabotropic glutamate receptor 5 and GABAB receptor) and on novel potential treatment acting on oxytocin system, which interacts with diverse neurotransmitters, has proved successful in both preclinical and clinical studies on ethanol, cocaine and methamphetamine. A crucial issue is the identification of new investigational paradigms, which may help to predict treatment efficacy and improve effectiveness.

PMID: 28874314 [PubMed - indexed for MEDLINE]

Related Articles

Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure.

Front Physiol. 2018;9:863

Authors: Shu C, Huang H, Xu Y, Rota M, Sorrentino A, Peng Y, Padera RF, Huntoon V, Agrawal PB, Liu X, Perrella MA

Abstract
Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family of proteins. Constitutive Speg deficient (Speg-/-) mice develop a dilated cardiomyopathy, and the majority of these mice die in utero or shortly after birth. In the present study we assessed the importance of Speg in adult mice. Speg-/- mice that survived to adulthood, or adult striated muscle-specific Speg knockout mice (Speg-KO), demonstrated cardiac dysfunction and evidence of increased left ventricular (LV) internal diameter and heart to body weight ratio. To determine whether heterozygosity of Speg interferes with the response of the heart to pathophysiologic stress, Speg+/- mice were exposed to pressure overload induced by transverse aortic constriction (TAC). At baseline, Speg+/+ and Speg+/- hearts showed no difference in cardiac function. However, 4 weeks after TAC, Speg+/- mice had a marked reduction in LV function. This defect was associated with an increase in LV internal diameter and enhanced heart weight to body weight ratio, compared with Speg+/+ mice after TAC. The response of Speg+/- mice to pressure overload also included increased fibrotic deposition in the myocardium, disruption of transverse tubules, and attenuation in cell contractility, compared with Speg+/+ mice. Taken together, these data demonstrate that Speg is necessary for normal cardiac function and is involved in the complex adaptation of the heart in response to TAC. Haploinsufficiency of Speg results in decompensated heart failure when exposed to pressure overload.

PMID: 30042693 [PubMed]

Premaxilla Stress Distribution and Bone Resorption Induced by Implant Overdenture and Conventional Denture.

J Prosthodont. 2018 Jul 25;:

Authors: Alsrouji MS, Ahmad R, Abdul Razak NH, Shuib S, Kuntjoro W, Baba NZ

Abstract
PURPOSE: To relate the principal stress, strain, and total deformation in the premaxilla region beneath a complete denture to the pattern of premaxilla bone resorption when opposed by a conventional complete denture (CD) or by a two-implant-retained overdenture (IOD) using finite element analysis (FEA).
MATERIALS AND METHODS: Three-dimensional solid models of the maxilla, mucosa, and denture of a selected edentulous patient were created using Mimics and CATIA software. The FEA model was created and duplicated in ANSYS 16.0 to perform two simulations for the IOD and the CD models. The values of maximum stress and strain and total deformation were obtained and compared to the outcomes of premaxilla resorption from a parallel clinical study.
RESULTS: The maximum principal stress in the premaxilla in the IOD model ranged from 0.019 to 0.336 MPa, while it ranged from 0.011 to 0.193 MPa in the CD model. The maximum principal strain in the IOD model was 1.75 times greater than that in the CD model. Total deformation was 1.8 times higher in the IOD model. Greater bone resorption was observed in regions of higher stress, which were on the occlusal and buccal sides of the premaxilla residual ridge.
CONCLUSION: Stress, strain, and total deformation values present in the premaxilla area beneath a CD were approximately two times greater in a comparison between an opposing mandibular two-IOD and an opposing mandibular CD. The results were consistent with a parallel clinical study in which the rate of premaxilla bone resorption was almost three times greater in the IOD group.

PMID: 30044033 [PubMed - as supplied by publisher]

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Pharmacogenomic study on anti-VEGF medicine in treatment of macular Neovascular diseases: a study protocol for a prospective observational study.

BMC Ophthalmol. 2018 Jul 24;18(1):181

Authors: Jing J, Yinchen S, Xia C, Jing W, Chong C, Xun X, Hengye H, Kun L

Abstract
BACKGROUND: Macular neovascular diseases can cause severe vision loss. A newly approved anti-VEGF drug Conbercept has shown good efficacy and safety in rigorous random controlled trials (RCT), however, it cannot fully reflect the clinical application of Conbercept in real world clinical practice. Moreover, anti-VEGF drugs are expensive and often require multiple treatments, and some patients have poor or even no response to the drugs,this resulted enormous waste of medical resources. Therefore, how to find out those patients who have good response, and how to develop individualized therapeutic regimen in real world need to be urgently investigated in the aspect of pharmacogenomics and pharmacometabolomics.
METHODS: This study is a multicenter, prospective, observational study of Conbecept treating macular neovascular diseases in China. Patients suffered from age-related macular degeneration, polypoidal choroidal vasculopathy, and pathological myopia who already planned to receive Conbercept treatment will be recruited. We aimed to enroll more than 5000 patients from 43 ophthalmic centers in China. Patients' clinical data and blood samples will be collected during the one-year follow-up period. Finally, the safety and efficacy of Conbercept, and the potential predictors of patients' response to Conbercept will be investigated by pharmacogenomics and pharmacometabolomics analysis.
DISCUSSION: This study will provide important data of Conbercept in treating macular neovascular diseases in real world. Besides, finding the predictor of patients' response will help doctor make more precise individualized therapeutic regimens.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT03128463 . Registered on 9 March 2017.

PMID: 30041608 [PubMed - in process]

Related Articles

Human liver spheroids in chemically defined conditions for studies of gene-drug, drug-drug and disease-drug interactions.

Pharmacogenomics. 2018 Jul 25;:

Authors: Ingelman-Sundberg M, Lauschke VM

Abstract
Recent phenotypically and functionally relevant human hepatic in vitro systems combine the ability to preserve interindividual molecular differences between patients' livers in culture with the accessibility and high-throughput compatibility of in vitro assays. These features facilitate studies of specific genetic polymorphisms by using cells from donors with defined variants of interest or by selective gene knock-down experiments. Furthermore, these models constitute promising tools to evaluate drug-drug interactions as well as the effects of liver diseases on drug pharmacokinetics in co-cultures of hepatocytes and non-parenchymal cells. In the near future, we anticipate that these tools will be of high relevance for predicting the in vivo kinetics, toxicity and drug-drug interactions of drug candidates already during preclinical development.

PMID: 30041575 [PubMed - as supplied by publisher]

Related Articles

Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies.

Pharmacogenomics. 2018 Jul 25;:

Authors: Raimondi A, Nichetti F, Peverelli G, Bartolomeo MD, Braud F, Pietrantonio F

Abstract
Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.

PMID: 30041572 [PubMed - as supplied by publisher]

Related Articles

Serum folate concentrations, asthma, atopy, and asthma control in Peruvian children.

Respir Med. 2017 Dec;133:29-35

Authors: Nicholson A, Pollard SL, Lima JJ, Romero KM, Tarazona-Meza C, Malpartida-Guzmán G, Mougey E, Hansel NN, Checkley W, GASP Study Investigators

Abstract
BACKGROUND: The relationship between folate status and asthma-related outcomes has not been carefully examined in low- and middle-income countries where folate deficiency is common.
METHODS: Ancillary analysis of an unmatched case-control study in which we analyzed serum folate concentrations in 412 children with asthma and 342 controls living in peri-urban communities in Lima, Peru. We examined baseline associations between folate and asthma, atopy, total serum IgE, pulmonary function, and fractional exhaled nitric oxide. We then followed children with asthma longitudinally for 6-9 months and assessed associations between folate and odds of uncontrolled asthma (defined as Asthma Control Test score ≤ 19) and of ≥1 emergency visits during follow-up.
RESULTS: A 10 ng/mL decrease in serum folate was associated with 45% higher adjusted odds of asthma (OR = 1.45, 95% CI 1.05-2.02). The folate-asthma relationship differed by atopic status: a 10 ng/mL decrease in serum folate was associated with a 2.4-fold higher odds of asthma among children without atopy (2.38, 1.20-4.72) and 23% higher odds of asthma in children with atopy (1.23, 0.85-1.80). Among children with asthma, a 10 ng/mL decrease in serum folate was associated with 62% higher odds of uncontrolled asthma (1.62, 1.02-2.56) and 73% higher odds of ≥1 emergency visits during follow-up (1.73, 1.05-2.85).
CONCLUSIONS: Serum folate concentrations were inversely associated with asthma, but this effect was stronger in children without atopy. Among children with asthma, lower serum folate concentrations were associated with higher risk of uncontrolled asthma.

PMID: 29173446 [PubMed - indexed for MEDLINE]

Related Articles

Cost Effectiveness of Genotype-Guided Warfarin Dosing in Patients with Mechanical Heart Valve Replacement Under the Fee-for-Service System.

Appl Health Econ Health Policy. 2017 Oct;15(5):657-667

Authors: Kim DJ, Kim HS, Oh M, Kim EY, Shin JG

Abstract
BACKGROUND: Although studies assessing the cost effectiveness of genotype-guided warfarin dosing for the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism have been reported, no publications have addressed genotype-guided warfarin therapy in mechanical heart valve replacement (MHVR) patients or genotype-guided warfarin therapy under the fee-for-service (FFS) insurance system.
OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of genotype-guided warfarin dosing in patients with MHVR under the FFS system from the Korea healthcare sector perspective.
METHODS: A decision-analytic Markov model was developed to evaluate the cost effectiveness of genotype-guided warfarin dosing compared with standard dosing. Estimates of clinical adverse event rates and health state utilities were derived from the published literature. The outcome measure was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed to explore the range of plausible results.
RESULTS: In a base-case analysis, genotype-guided warfarin dosing was associated with marginally higher QALYs than standard warfarin dosing (6.088 vs. 6.083, respectively), at a slightly higher cost (US$6.8) (year 2016 values). The ICER was US$1356.2 per QALY gained. In probabilistic sensitivity analysis, there was an 82.7% probability that genotype-guided dosing was dominant compared with standard dosing, and a 99.8% probability that it was cost effective at a willingness-to-pay threshold of US$50,000 per QALY gained.
CONCLUSION: Compared with only standard warfarin therapy, genotype-guided warfarin dosing was cost effective in MHVR patients under the FFS insurance system.

PMID: 28247199 [PubMed - indexed for MEDLINE]

Inhibition of endocytosis suppresses the nitric oxide-dependent release of Cl- in retinal amacrine cells.

PLoS One. 2018;13(7):e0201184

Authors: Dunn VK, Gleason E

Abstract
Our lab has previously shown that nitric oxide (NO) can alter the synaptic response properties of amacrine cells by releasing Cl- from internal acidic compartments. This alteration in the Cl- gradient brings about a positive shift in the reversal potential of the GABA-gated current, which can convert inhibitory synapses into excitatory synapses. Recently, we have shown that the cystic fibrosis transmembrane regulator (CFTR) Cl- channel is involved in the Cl- release. Here, we test the hypothesis that (acidic) synaptic vesicles are a source of NO-releasable Cl- in chick retinal amacrine cells. If SVs are a source of Cl-, then depleting synaptic vesicles should decrease the nitric oxide-dependent shift in the reversal potential of the GABA-gated current. The efficacy of four inhibitors of dynamin (dynasore, Dyngo 4a, Dynole 34-2, and MiTMAB) were evaluated. In order to deplete synaptic vesicles, voltage-steps were used to activate V-gated Ca2+ channels and stimulate the synaptic vesicle cycle either under control conditions or after treatment with the dynamin inhibitors. Voltage-ramps were used to measure the NO-dependent shift in the reversal potential of the GABA-gated currents under both conditions. Our results reveal that activating the synaptic vesicle cycle in the presence of dynasore or Dyngo 4a blocked the NO-dependent shift in EGABA. However, we also discovered that some dynamin inhibitors reduced Ca2+ signaling and L-type Ca2+ currents. Conversely, dynasore also increased neurotransmitter release at autaptic sites. To further resolve the mechanism underlying the inhibition of the NO-dependent shift in the reversal potential for the GABA-gated currents, we also tested the effects of the clathrin assembly inhibitor Pitstop 2 and found that this compound also inhibited the shift. These data provide evidence that dynamin inhibitors have multiple effects on amacrine cell synaptic transmission. These data also suggest that inhibition of endocytosis disrupts the ability of NO to elicit Cl- release from internal stores which may in part be due to depletion of synaptic vesicles.

PMID: 30044876 [PubMed - in process]

Children With Cystic Fibrosis May Be Performing Oscillating Positive Expiratory Pressure Therapy Incorrectly.

Chest. 2018 Jul;154(1):231-232

Authors: O'Sullivan KJ, Collins L, McGrath D, Linnane B, O'Sullivan L, Dunne CP

PMID: 30044744 [PubMed - in process]

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The Pseudomonas aeruginosa PilSR Two-Component System Regulates Both Twitching and Swimming Motilities.

MBio. 2018 Jul 24;9(4):

Authors: Kilmury SLN, Burrows LL

Abstract
Motility is an important virulence trait for many bacterial pathogens, allowing them to position themselves in appropriate locations at appropriate times. The motility structures type IV pili and flagella are also involved in sensing surface contact, which modulates pathogenicity. In Pseudomonas aeruginosa, the PilS-PilR two-component system (TCS) regulates expression of the type IV pilus (T4P) major subunit PilA, while biosynthesis of the single polar flagellum is regulated by a hierarchical system that includes the FleSR TCS. Previous studies of Geobacter sulfurreducens and Dichelobacter nodosus implicated PilR in regulation of non-T4P-related genes, including some involved in flagellar biosynthesis. Here we used transcriptome sequencing (RNA-seq) analysis to identify genes in addition to pilA with changes in expression in the absence of pilR Among the genes identified were 10 genes whose transcription increased in the pilA mutant but decreased in the pilR mutant, despite both mutants lacking T4P and pilus-related phenotypes. The products of these inversely dysregulated genes, many of which were hypothetical, may be important for virulence and surface-associated behaviors, as mutants had altered swarming motility, biofilm formation, type VI secretion system expression, and pathogenicity in a nematode model. Further, the PilSR TCS positively regulated transcription of fleSR, and thus many genes in the FleSR regulon. As a result, pilSR deletion mutants had defects in swimming motility that were independent of the loss of PilA. Together, these data suggest that in addition to controlling T4P expression, PilSR could have a broader role in the regulation of P. aeruginosa motility and surface sensing behaviors.IMPORTANCE Surface appendages such as type IV pili and flagella are important for establishing surface attachment and infection in a host in response to appropriate cues. The PilSR regulatory system that controls type IV pilus expression in Pseudomonas aeruginosa has an established role in expression of the major pilin PilA. Here we provide evidence supporting a new role for PilSR in regulating flagellum-dependent swimming motility in addition to pilus-dependent twitching motility. Further, even though both pilA and pilR mutants lack PilA and pili, we identified sets of genes downregulated in the pilR mutant and upregulated in a pilA mutant as well as genes downregulated only in a pilR mutant, independent of pilus expression. This finding suggests that change in the inner membrane levels of PilA is only one of the cues to which PilR responds to modulate gene expression. Identification of PilR as a regulator of multiple motility pathways may make it an interesting therapeutic target for antivirulence compounds.

PMID: 30042200 [PubMed - in process]

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Clinical Deterioration Due to Exophiala Dermatitidis in a Patient with Cystic Fibrosis.

Arch Bronconeumol. 2018 Jul 02;:

Authors: Martín Ramírez A, Erro Iribarren M, Buendía Moreno B, María Girón R

PMID: 30041956 [PubMed - as supplied by publisher]