Related Articles

Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia.

NPJ Genom Med. 2017 Apr 14;2:12

Authors: Ahmadi S, Bozoky Z, Di Paola M, Xia S, Li C, Wong AP, Wellhauser L, Molinski SV, Ip W, Ouyang H, Avolio J, Forman-Kay JD, Ratjen F, Hirota JA, Rommens J, Rossant J, Gonska T, Moraes TJ, Bear CE

Abstract
Pulmonary disease is the major cause of morbidity and mortality in patients with cystic fibrosis, a disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Heterogeneity in CFTR genotype-phenotype relationships in affected individuals plus the escalation of drug discovery targeting specific mutations highlights the need to develop robust in vitro platforms with which to stratify therapeutic options using relevant tissue. Toward this goal, we adapted a fluorescence plate reader assay of apical CFTR-mediated chloride conductance to enable profiling of a panel of modulators on primary nasal epithelial cultures derived from patients bearing different CFTR mutations. This platform faithfully recapitulated patient-specific responses previously observed in the "gold-standard" but relatively low-throughput Ussing chamber. Moreover, using this approach, we identified a novel strategy with which to augment the response to an approved drug in specific patients. In proof of concept studies, we also validated the use of this platform in measuring drug responses in lung cultures differentiated from cystic fibrosis iPS cells. Taken together, we show that this medium throughput assay of CFTR activity has the potential to stratify cystic fibrosis patient-specific responses to approved drugs and investigational compounds in vitro in primary and iPS cell-derived airway cultures.

PMID: 28649446 [PubMed - in process]

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Evolutionary adaptations of biofilms infecting cystic fibrosis lungs promote mechanical toughness by adjusting polysaccharide production.

NPJ Biofilms Microbiomes. 2017;3:1

Authors: Kovach K, Davis-Fields M, Irie Y, Jain K, Doorwar S, Vuong K, Dhamani N, Mohanty K, Touhami A, Gordon VD

Abstract
Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances, largely polysaccharides. Multiple types of extracellular polymeric substances can be produced by a single bacterial strain. The distinct polymer components of biofilms are known to provide chemical protection, but little is known about how distinct extracellular polysaccharides may also protect biofilms against mechanical stresses such as shear or phagocytic engulfment. Decades-long infections of Pseudomonas. aeruginosa biofilms in the lungs of cystic fibrosis patients are natural models for studies of biofilm fitness under pressure from antibiotics and the immune system. In cystic fibrosis infections, production of the extracellular polysaccharide alginate has long been known to increase with time and to chemically protect biofilms. More recently, it is being recognized that chronic cystic fibrosis infections also evolve to increase production of another extracellular polysaccharide, Psl; much less is known about Psl's protective benefits to biofilms. We use oscillatory bulk rheology, on biofilms grown from longitudinal clinical isolates and from genetically-manipulated lab strains, to show that increased Psl stiffens biofilms and increases biofilm toughness, which is the energy cost to cause the biofilm to yield mechanically. Further, atomic force microscopy measurements reveal greater intercellular cohesion for higher Psl expression. Of the three types of extracellular polysaccharides produced by P. aeruginosa, only Psl increases the stiffness. Stiffening by Psl requires CdrA, a protein that binds to mannose groups on Psl and is a likely cross-linker for the Psl components of the biofilm matrix. We compare the elastic moduli of biofilms to the estimated stresses exerted by neutrophils during phagocytosis, and infer that increased Psl could confer a mechanical protection against phagocytic clearance.

PMID: 28649402 [PubMed - in process]

Related Articles

Ecological networking of cystic fibrosis lung infections.

NPJ Biofilms Microbiomes. 2016;2:4

Authors: Quinn RA, Whiteson K, Lim YW, Zhao J, Conrad D, LiPuma JJ, Rohwer F, Widder S

Abstract
In the context of a polymicrobial infection, treating a specific pathogen poses challenges because of unknown consequences on other members of the community. The presence of ecological interactions between microbes can change their physiology and response to treatment. For example, in the cystic fibrosis lung polymicrobial infection, antimicrobial susceptibility testing on clinical isolates is often not predictive of antibiotic efficacy. Novel approaches are needed to identify the interrelationships within the microbial community to better predict treatment outcomes. Here we used an ecological networking approach on the cystic fibrosis lung microbiome characterized using 16S rRNA gene sequencing and metagenomics. This analysis showed that the community is separated into three interaction groups: Gram-positive anaerobes, Pseudomonas aeruginosa, and Staphylococcus aureus. The P. aeruginosa and S. aureus groups both anti-correlate with the anaerobic group, indicating a functional antagonism. When patients are clinically stable, these major groupings were also stable, however, during exacerbation, these communities fragment. Co-occurrence networking of functional modules annotated from metagenomics data supports that the underlying taxonomic structure is driven by differences in the core metabolism of the groups. Topological analysis of the functional network identified the non-mevalonate pathway of isoprenoid biosynthesis as a keystone for the microbial community, which can be targeted with the antibiotic fosmidomycin. This study uses ecological theory to identify novel treatment approaches against a polymicrobial disease with more predictable outcomes.

PMID: 28649398 [PubMed - in process]

Related Articles

Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis.

Eur Clin Respir J. 2017;4(1):1318027

Authors: Kongstad T, Green K, Buchvald F, Skov M, Pressler T, Nielsen KG

Abstract
Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections (N = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% (p < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions: The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed.

PMID: 28649308 [PubMed - in process]

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The use of fructosamine in cystic fibrosis-related diabetes (CFRD) screening.

J Cyst Fibros. 2017 Jun 22;:

Authors: Lam GY, Doll-Shankaruk M, Dayton J, Rodriguez-Capote K, Higgins TN, Thomas D, Mulchey K, Smith MP, Brown NE, Leung WM, Estey MP

Abstract
OBJECTIVE: To determine whether serum fructosamine correlates with glycemic control and clinical outcomes in patients being screened for cystic fibrosis-related diabetes (CFRD).
METHODS: Fructosamine and percent predicted forced expiratory volume in 1s (FEV1) were measured in patients undergoing a 2h oral glucose tolerance test (OGTT) for CFRD screening. Fractional serum fructosamine (FSF) was calculated as fructosamine/total protein.
RESULTS: FSF exhibited a positive correlation with 2h OGTT results (r(2)=0.3201, p=0.009), and ROC curve analysis suggested that FSF can identify patients with an abnormal OGTT (AUC=0.840, p=0.0002). FSF also exhibited a negative correlation with FEV1 (r(2)=0.3732, p=0.035). Patients with FSF≥3.70μmol/g had significantly lower FEV1 (median 47%) compared to those with FSF<3.70μmol/g (median 90%; p=0.015).
CONCLUSIONS: FSF correlated with both OGTT results and FEV1, and reliably identified patients with abnormal OGTT results. This simple blood test shows potential as an effective tool in CFRD screening.

PMID: 28648493 [PubMed - as supplied by publisher]

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Suspicion of respiratory tract infection with multidrug-resistant Enterobacteriaceae: epidemiology and risk factors from a Paediatric Intensive Care Unit.

BMC Infect Dis. 2017 Feb 21;17(1):163

Authors: Renk H, Stoll L, Neunhoeffer F, Hölzl F, Kumpf M, Hofbeck M, Hartl D

Abstract
BACKGROUND: Multidrug-resistant (MDR) infections are a serious concern for children admitted to the Paediatric Intensive Care Unit (PICU). Tracheal colonization with MDR Enterobacteriaceae predisposes to respiratory infection, but underlying risk factors are poorly understood. This study aims to determine the incidence of children with suspected infection during mechanical ventilation and analyses risk factors for the finding of MDR Enterobacteriaceae in tracheal aspirates.
METHODS: A retrospective single-centre analysis of Enterobacteriaceae isolates from the lower respiratory tract of ventilated PICU patients from 2005 to 2014 was performed. Resistance status was determined and clinical records were reviewed for potential risk factors. A classification and regression tree (CRT) to predict risk factors for infection with MDR Enterobacteriaceae was employed. The model was validated by simple and multivariable logistic regression.
RESULTS: One hundred sixty-seven Enterobacteriaceae isolates in 123 children were identified. The most frequent isolates were Enterobacter spp., Klebsiella spp. and E.coli. Among these, 116 (69%) isolates were susceptible and 51 (31%) were MDR. In the CRT analysis, antibiotic exposure for ≥ 7 days and presence of gastrointestinal comorbidity were the most relevant predictors for an MDR isolate. Antibiotic exposure for ≥ 7 days was confirmed as a significant risk factor for infection with MDR Enterobacteriaceae by a multivariable logistic regression model.
CONCLUSIONS: This study shows that critically-ill children with tracheal Enterobacteriaceae infection are at risk of carrying MDR isolates. Prior use of antibiotics for ≥ 7 days significantly increased the risk of finding MDR organisms in ventilated PICU patients with suspected infection. Our results imply that early identification of patients at risk, rapid microbiological diagnostics and tailored antibiotic therapy are essential to improve management of critically ill children infected with Enterobacteriaceae.

PMID: 28222699 [PubMed - indexed for MEDLINE]

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Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE.

JAMA Pediatr. 2016 Jun 01;170(6):562-9

Authors: Kumar S, Ooi CY, Werlin S, Abu-El-Haija M, Barth B, Bellin MD, Durie PR, Fishman DS, Freedman SD, Gariepy C, Giefer MJ, Gonska T, Heyman MB, Himes R, Husain SZ, Lin TK, Lowe ME, Morinville V, Palermo JJ, Pohl JF, Schwarzenberg SJ, Troendle D, Wilschanski M, Zimmerman MB, Uc A

Abstract
IMPORTANCE: Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood.
OBJECTIVE: To characterize and identify risk factors associated with ARP and CP in childhood.
DESIGN, SETTING, AND PARTICIPANTS: A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test.
MAIN OUTCOMES AND MEASURES: Demographic characteristics, risk factors, abdominal pain, and disease burden.
RESULTS: A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions).
CONCLUSIONS AND RELEVANCE: Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.

PMID: 27064572 [PubMed - indexed for MEDLINE]

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.

Am J Med Genet A. 2017 Jun 26;:

Authors: Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN, Tang S, Srivastava S, Pevsner J, Trifunovic A, Fatemi A

Abstract
Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.

PMID: 28650581 [PubMed - as supplied by publisher]

The genetics of platelet count and volume in humans.

Platelets. 2017 Jun 26;:1-6

Authors: Eicher JD, Lettre G, Johnson AD

Abstract
The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet's role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies-ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)-employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.

PMID: 28649937 [PubMed - as supplied by publisher]

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Novel 25 kb Deletion of MERTK Causes Retinitis Pigmentosa With Severe Progression.

Invest Ophthalmol Vis Sci. 2017 Mar 01;58(3):1736-1742

Authors: Evans DR, Green JS, Johnson GJ, Schwartzentruber J, Majewski J, Beaulieu CL, Qin W, Marshall CR, Paton TA, Roslin NM, Paterson AD, Fahiminiya S, French J, Boycott KM, Woods MO, FORGE Canada Consortium

Abstract
Purpose: Retinitis pigmentosa (RP) describes a complex group of inherited retinal dystrophies with almost 300 reported genes and loci. We investigated the genetic etiology of autosomal recessive RP (arRP) in a large kindred with 5 affected family members, who reside on the island of Newfoundland, Canada.
Methods: Genetic linkage analysis was performed on 12 family members (Infinium HumanOmni2.5-8 BeadChip). Whole exome sequencing analysis (Illumina HiSeq) was performed on one affected individual. A custom pipeline was applied to call, annotate, and filter variants. FishingCNV was used to scan the exome for rare copy number variants (CNVs). Candidate CNVs subsequently were visualized from microarray data (CNVPartition v.3.1.6.). MERTK breakpoints were mapped and familial cosegregation was tested using Sanger Sequencing.
Results: We found strong evidence of linkage to a locus on chromosome 2 (logarithm of the odds [LOD] 4.89 [θ = 0]), at an interval encompassing the MERTK gene. Whole exome sequencing did not uncover candidate point mutations in MERTK, or other known RP genes. Subsequently, CNV analysis of the exome data and breakpoint mapping revealed a 25,218 bp deletion of MERTK, encompassing exons 6 to 8, with breakpoints in introns 5 (chr2:112,725,292) and 8 (chr2:112,750,421). A 48 bp insertion sequence was buried within the breakpoint; 18 bps shared homology to MIR4435-2HG and LINC00152, and 30 bp mapped to MERTK. The deletion cosegregated with arRP in the family.
Conclusions: This study describes the molecular and clinical characterization of an arRP family segregating a novel 25 kb deletion of MERTK. These findings may assist clinicians in providing a diagnosis for other unsolved RP cases.

PMID: 28324114 [PubMed - indexed for MEDLINE]

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Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology.

Dev Biol. 2016 Jul 15;415(2):216-227

Authors: Palmer K, Fairfield H, Borgeia S, Curtain M, Hassan MG, Dionne L, Yong Karst S, Coombs H, Bronson RT, Reinholdt LG, Bergstrom DE, Donahue LR, Cox TC, Murray SA

Abstract
Craniofacial abnormalities are among the most common features of human genetic syndromes and disorders. The etiology of these conditions is often complex, influenced by both genetic context and the environment. Frequently, craniofacial abnormalities present as part of a syndrome with clear comorbid phenotypes, providing additional insight into mechanisms of the causative gene or pathway. The mouse has been a key tool in our understanding of the genetic mechanisms of craniofacial development and disease, and can provide excellent models for human craniofacial abnormalities. While powerful genetic engineering tools in the mouse have contributed significantly our understanding of craniofacial development and dysmorphology, forward genetic approaches provide an unbiased means to identify new genes and pathways. Moreover, spontaneous mutations can occur on any number of genetic backgrounds, potentially revealing critical genes that require a specific genetic context. Here we report discovery and phenotyping of 43 craniofacial mouse models, derived primarily from a screen for spontaneous mutations in production colonies at the Jackson Laboratory. We identify the causative gene for 33 lines, including novel genes in pathways not previously connected to craniofacial development, and novel alleles of known genes that present with unique phenotypes. Together with our detailed characterization, this work provides a valuable gene discovery resource for the craniofacial community, and a rich source of mouse models for further investigation.

PMID: 26234751 [PubMed - indexed for MEDLINE]

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Notice NOT-OD-17-084 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-FD-17-013 from the NIH Guide for Grants and Contracts. The Food and Drug Administration (FDA) is announcing the availability of cooperative agreement funds for the support of a Funding Opportunity Announcement (FOA) entitled "Academic Development of a Training Program for Good Laboratory Practices in High Containment Environments (U24).' In this FOA, FDA announces its intention to accept and consider a single source application for an award to the University of Texas Medical Branch (UTMB) Galveston National Laboratory (GNL) for the development and implementation of a certified, academic training course for instruction in Good Laboratory Practices (GLP) in a Biosafety Level (BSL) 4 High Containment Environment. FDA seeks to support an effort to design a robust, collaborative, and educational program using problem-based learning techniques designed to bring researchers and regulators together to educate each other on the challenges related to these issues and to identify solutions that are acceptable from both scientific and regulatory perspectives.

Funding Opportunity RFA-FD-17-014 from the NIH Guide for Grants and Contracts. The goals of this program are to support the development of the scientific infrastructure needed to plan and execute pediatric clinical trials through collaboration with stakeholders from academia, industry, parent/patient advocacy groups, and government agencies. The Global Pediatric Trial Network should be a coordinating resource for pediatric product development with sustainable global infrastructure to plan, start up, conduct, and close out pediatric clinical investigations. There should be an emphasis on operational efficiency and network sustainability with early, systematic, and integrative approaches to pediatric studies.

Funding Opportunity RFA-AT-17-003 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA), issued by the National Center for Complementary and Integrative Health (NCCIH), seeks to solicit limited applications for continuation of an established research resource consisting of a database of primary reports of the full spectrum of complementary and integrative health controlled clinical trials. This resource will facilitate the conduct of high quality systematic reviews and when possible meta-analyses of published reports of clinical trials of complementary and integrative health treatments and interventions. The review of all published controlled clinical trials on a given topic and summary of the results in a systematic and unbiased manner provide a current best evidence for health care practitioners, patients, health care policy makers and research administration. In addition, the resource will ensure and promote access and availability to the broader scientific community and provide editorial, methodological and technical support to those utilizing the resource for systematic reviews. Applications must address the following: justification regarding why continued funding is needed from NIH; plans for maintenance of a research resource consisting of a complementary and integrative health controlled clinical trials database; plans to ensure access and availability of the resource to the scientific community; address updates of current reviews in the database; conduct of a minimum of one new and update two existing NCCIH strategic plan-related systematic reviews per year and when possible meta-analyses; and methods the investigators will use to identify new reviews and updates that align with NCCIH strategic priorities, particularly evaluating the effectiveness of mind and body complementary interventions for pain conditions.

Funding Opportunity RFA-HG-17-006 from the NIH Guide for Grants and Contracts. The National Human Genome Research Institute (NHGRI) is soliciting grant applications for the support of Centers of Excellence in Ethical, Legal and Social Implications (ELSI) Research (CEERs). The CEER Program is designed to support the establishment of sustainable trans-disciplinary research teams with the expertise and flexibility to anticipate, conduct research on, and quickly address a range of cutting edge ethical, legal, and social issues related to genetics and genomics. The Program is intended to create new research opportunities that cross disciplinary boundaries among investigators in diverse fields, such as the genomic sciences, clinical research, clinical and health policy, ethics, law, the humanities, economics, political science, anthropology and other social sciences. In addition to conducting trans-disciplinary research, Centers will disseminate their research findings as well as facilitate the use of their findings to develop relevant research, health and public policies and practices. Finally, Centers will contribute to developing the next generation of ELSI researchers.

In vivo phenotypic screening: clinical proof of concept for a drug repositioning approach.

Drug Discov Today Technol. 2017 Mar;23:45-52

Authors: Ciallella JR, Reaume AG

Abstract
In vivo phenotypic screening and drug repositioning are strategies developed as alternatives to underperforming hypothesis-driven molecular target based drug discovery efforts. This article reviews examples of drugs identified by phenotypic observations and describes the use of the theraTRACE(®)in vivo screening platform for finding and developing new indications for discontinued clinical compounds. Clinical proof-of-concept for the platform is exemplified by MLR-1023, a repositioned compound that has recently shown significant clinical efficacy in Type 2 diabetes patients. These findings validate an in vivo screening approach for drug development and underscore the importance of alternatives to target and mechanism based strategies that have failed to produce adequate numbers of new medicines.

PMID: 28647085 [PubMed - in process]