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Cambridge, MA, United States

Adoue V.,French Institute of Health and Medical Research | Schiavi A.,McGill University | Light N.,McGill University | Almlof J.C.,Uppsala University | And 19 more authors.
Molecular Systems Biology | Year: 2014

Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases. © 2014 The Authors. Source

Davidson L.R.R.,National CJD Research and Surveillance Unit | Llewelyn C.A.,Cambridge Center | Mackenzie J.M.,National CJD Research and Surveillance Unit | Hewitt P.E.,Colindale Center | Will R.G.,National CJD Research and Surveillance Unit
Vox Sanguinis | Year: 2014

Background and Objectives: In this study, we compare variant Creutzfeldt-Jakob disease (vCJD) cases definitely linked to blood transfusion, those with a history of blood transfusion in which no donor has developed vCJD and primary cases with no history of blood transfusion. The aim is to determine whether there are any differences in the demographics or clinical phenotype in these groups that might suggest additional cases of transfusion transmission of vCJD. Materials and Methods: All cases of vCJD who are old enough to donate blood (i.e. >17 years old) are notified to the UKBTS at diagnosis, regardless of whether they are known to have a blood donation history. A search is then made for donor records and, if found, all components produced and issued to hospitals are identified and their fate determined. Recipient details are then checked against the NCJDRSU register to establish whether there is a match between these individuals and patients who have been diagnosed with vCJD. In the reverse study, attempts are made to trace the donors to all cases reported to have received a blood transfusion and donors' details are checked against the register to determine if any have developed vCJD. Results: Of the 177 cases of vCJD diagnosed in the UK as of 1 February 2014, the TMER study identified 15 cases reported to have received a blood transfusion. Transfusion records were unavailable for 4 of these cases, all pre-1980, and in one other case there was no transfusion recorded in the medical notes. Transfusion records were found for 10 cases. One case transfused at symptom onset was excluded from this analysis. The mean age at onset of symptoms of the remaining nine transfusion recipients (four female and five male) was 42·9 years; 57·6 years in the three known transfusion-transmitted cases and 35·5 years in the six not linked cases. In one of these cases, details of components transfused were unavailable, and the remaining five cases received a total of 116 donor exposures with 112 donors identified, none of whom is known to have developed clinical vCJD. To date, five of the 112 identified donors have died and none was certified as dying of vCJD or any other neurological disorder. Two of the transfusion-transmitted cases did not fulfil diagnostic criteria for probable vCJD during life but were confirmed at post-mortem. Both cases were in the older age range (68 and 74 years, respectively), and neither had a positive MRI brain scan. The remaining cases all fulfilled the criteria for the diagnosis of vCJD in life, but two of these had atypical features and were older than the expected age at onset for vCJD. Conclusion: In conclusion, it is possible that one or more of the vCJD cases that received a blood transfusion derived from an individual not known to have vCJD were infected by the blood transfusion. However, the evidence for this is weak, and the absence of a past history of transfusion in most cases of vCJD excludes a large number of unrecognised transfusion-transmitted cases. © 2014 International Society of Blood Transfusion. Source

White J.T.,Biogen | Kieseier B.C.,Biogen | Kieseier B.C.,Heinrich Heine University Dusseldorf | Bermel R.A.,Cleveland Clinic | And 5 more authors.
Therapeutic Advances in Neurological Disorders | Year: 2016

Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Methods: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity. © SAGE Publications. Source

Hinkle D.M.,Cambridge Center | Dacey M.S.,Margolis Vision | Mandelcorn E.,Uptown Eye Specialists | Kalyani P.,Jules Stein Eye Institute | And 8 more authors.
Cutaneous and Ocular Toxicology | Year: 2012

Context: Retrospective case series, database study and literature review. Forty case reports are described. Objective: To report a possible association between fluoroquinolones and uveitis. Materials and Methods: Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization, and Food and Drug Administration were collected on uveitis associated with systemic fluoroquinolone therapy. A literature review was performed using keywords "uveitis", "fluoroquinolones", and each individual fluoroquinolone name. Additional case reports were collected from the practices of six uveitis subspecialists and one neuro-ophthalmologist. Main Outcome Measures: Data garnered from the reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of uveitis, concomitant drugs, systemic disease, dechallenge and rechallenge data. Results: A total of 40 case reports of uveitis associated with fluoroquinolones were identified including 12 men, 27 women, and 1 case in which the gender was not specified. The median age was 54 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 13 days (range 020 days). Thirteen patients were 60 years or older, and one patient was taking systemic anti-inflammatory steroids. There were five positive dechallenge case reports. Discussion: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and uveitis is "possible" . Causality assessments are based on the time relationship of drug administration, uveitis development, and dechallenge data. Conclusions: Clinicians should be aware of a possible bilateral fluoroquinolone-associated uveitis, particularly the finding of iris transillumination and pigment dispersion. © 2012 Informa Healthcare USA, Inc. Source

Metzinger J.L.,Massachusetts Eye Research and Surgery Institution | Metzinger J.L.,Cambridge Center | Foster C.S.,Massachusetts Eye Research and Surgery Institution | Foster C.S.,Cambridge Center | Foster C.S.,Harvard University
Expert Opinion on Orphan Drugs | Year: 2015

Uveitis, a leading cause of preventable blindness around the world, is a critically underserved indication with regard to medications approved for use. Appropriate therapy routines for uveitis often involve a combination of corticosteroid and immunomodulating chemotherapies, dependent on patient presentation and diagnosis, clinical response and observed side effects, if any. Obtaining many of these medications can involve a lengthy appeals process after insurance denial, as all corticosteroid-sparing immunomodulatory therapies are utilized in an 'off-label' fashion.Areas covered: The purpose of this manuscript is to comprehensively review the current status of medications approved for use in uveitis: those that hold approval currently, and those that are undergoing clinical trials in the indication of uveitis. Additionally, points of consideration for clinical development-specifically with regard to clinically meaningful end points-are discussed.Expert opinion: Determination of clinically meaningful end points, which may entail revisiting the current clinical assessments used to determine efficacy, is crucial to future drug development with regard to uveitis. Approval in this indication may potentially expand access to pharmacologics for the treatment of this orphan disease. © 2015 Informa UK, Ltd. Source

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