| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
- Naldi, Luigi, et al.
(författare)
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Prevalence of Self-reported Skin Complaints and Avoidance of Common Daily Life Consumer Products in Selected European Regions.
- 2014
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Ingår i: JAMA Dermatology. - : American Medical Association (AMA). - 2168-6084 .- 2168-6068. ; 150:2, s. 154-162
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Skin disorders are common in the general population, and they may be associated with significant disability. The use of daily skin products may affect the appearance and severity of skin conditions. OBJECTIVES To assess the prevalence of reported itchy rash lasting longer than 3 days among the general population and to evaluate lifetime avoidance of different types of consumer products because of skin problems. DESIGN, SETTING, AND PARTICIPANTS The European Dermato-Epidemiology Network (EDEN) Fragrance Study comprised a large descriptive epidemiological survey of the general population conducted in 6 European regions from August 20, 2008, to October 10, 2011. Participants were a random sample of individuals aged 18 to 74 years, based on electoral precincts. The participants were interviewed using a standardized questionnaire. EXPOSURES Lifetime exposure to products of common use was considered, including toiletry items that remained on the skin or were rinsed off and household and functional items. MAIN OUTCOMES AND MEASURES The 1-month, 1-year, and lifetime age-standardized prevalence rates of itchy rash that lasted longer than 3 days. RESULTS In total, 12 377 individuals (53.9% female; median age, 43 years) were interviewed. The overall prevalences of itchy rash were 19.3% (95% CI, 18.6%-20.0%) during the month preceding the interview, 31.8% (95% CI, 31.0%-32.6%) during the preceding year, and 51.7% (95% CI, 50.8%-52.6%) over a lifetime. In addition, the percentage of individuals who reported avoidance of any product varied from 37.0% for products intended to be left on the skin to 17.7% for household or functional products. CONCLUSIONS AND RELEVANCE Our findings confirmed the magnitude of skin problems among the general population reported in other surveys. Although itchy rash is a nonspecific manifestation, it may be considered in epidemiological surveys to reflect a constellation of skin conditions and to summarize the burden of these conditions on general health.
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| 3. |
- Parenti, Marco Daniele, et al.
(författare)
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Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
- 2022
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 243
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings support the hypothesis that inhibition of SMYD3 methyltransferase may be a therapeutic avenue for some of the deadliest cancer types. Herein, active site-selective covalent SMYD3 inhibitors were designed by introducing an appropriate reactive cysteine trap into reversible first-generation SMYD3 inhibitors. The 4-amino-piperidine derivative EM127 (11C) bearing a 2-chloroethanoyl group as reactive warhead showed selectivity for Cys186, located in the substrate/histone binding pocket. Selectivity towards Cys186 was retained even at high inhibitor/enzyme ratio, as shown by mass spectrometry. The mode of interaction with the SMYD3 substrate/ histone binding pocket was revealed by crystallographic studies. In enzymatic assays, 11C showed a stronger SMYD3 inhibitory effect compared to the reference inhibitor EPZ031686. Remarkably, 11C attenuated the proliferation of MDA-MB-231 breast cancer cell line at the same low micromolar range of concentrations that reduced SMYD3 mediated ERK signaling in HCT116 colorectal cancer and MDA-MB-231 breast cancer cells. Furthermore, 11C (5 mu M) strongly decreased the steady-state mRNA levels of genes important for tumor biology such as cyclin dependent kinase 2, c-MET, N-cadherin and fibronectin 1, all known to be regulated, at least in part, by SMYD3. Thus, 11C is as a first example of second generation SMYD3 inhibitors; this agent represents a covalent and a site specific SMYD3 binder capable of potent and prolonged attenuation of methyltransferase activity.
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| 4. |
- Talibov, Vladimir O, 1991-, et al.
(författare)
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Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase
- 2021
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
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Tidskriftsartikel (refereegranskat)abstract
- SMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 ÎŒM). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although HSP90-SMYD3 binding was confirmed ( K D = 13 ÎŒM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action.
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