Plasmacytoid predendritic cells initiate psoriasis through interferon-α production

Psoriasis is one of the most common T cell–mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-α–producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-α early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-α signaling or inhibiting the ability of PDCs to produce IFN-α prevented the T cell–dependent development of psoriasis. Furthermore, IFN-α reconstitution experiments demonstrated that PDC-derived IFN-α is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-α represent potential early targets for the treatment of psoriasis

Discovery of Highly Potent and Selective CXCR4 Inhibitors Using Protein Epitope Mimetics (PEM) Technology

Novel, highly potent CXCR4 inhibitors with good pharmacokinetic properties were obtained by applying PEM technology starting from the naturally occurring ?-hairpin peptide polyphemusin II. The design involved incorporation of key residues from polyphemusin II into a macrocyclic template-bound ?-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized, resulting in CXCR4 inhibitors such as POL2438 and POL3026. Their activities were confirmed in a series of in vitro HIV-1 infection assays. Besides high selectivity for CXCR4, POL3026 had excellent plasma stability and favorable pharmacokinetic properties in dogs. In a murine model POL3026 was highly efficacious in hematopoietic stem cell mobilization. Hence, PEM-based CXCR4 inhibitors have the potential to become therapeutic agents for the treatment of HIV infections (as entry inhibitor), cancer (e.g. for inhibition of metastasis), stem cell transplant and inflammation

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Introduction:The longitudinal trajectories of functional brain dynamics and the impact of geneticrisk factors in individuals at risk for Alzheimer\u2019s disease are poorly understood.Methods:In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk forAlzheimer\u2019s disease, default mode network (DMN) resting state functional connectivity (FC) wasinvestigated between two serial time points across 2 years.Results:Widespread DMN FC changes were shown in frontal and posterior areas, as well as in theright hippocampus. There were no cross-sectional differences, however, apolipoprotein E\u3b54(APOE\u3b54) carriers demonstrated slower increase in FC in frontal lobes. There was no impact ofindividual brain amyloid load status.Discussion:For the first time, we demonstrated that the pleiotropic biological effect of theAPOE\u3b54allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkersmay become useful surrogate outcomes for the development of preclinical targeted therapeuticinterventions

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

147siIntroduction Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.partially_openopenVergallo A.; Bun R.-S.; Toschi N.; Baldacci F.; Zetterberg H.; Blennow K.; Cavedo E.; Lamari F.; Habert M.-O.; Dubois B.; Floris R.; Garaci F.; Lista S.; Hampel H.; Audrain C.; Auffret A.; Bakardjian H.; Baldacci F.; Batrancourt B.; Benakki I.; Benali H.; Bertin H.; Bertrand A.; Boukadida L.; Cacciamani F.; Causse V.; Cavedo E.; Cherif Touil S.; Chiesa P.A.; Colliot O.; Dalla Barba G.; Depaulis M.; Dos Santos A.; Dubois B.; Dubois M.; Epelbaum S.; Fontaine B.; Francisque H.; Gagliardi G.; Genin A.; Genthon R.; Glasman P.; Gombert F.; Habert M.O.; Hampel H.; Hewa H.; Houot M.; Jungalee N.; Kas A.; Kilani M.; La Corte V.; Le Roy F.; Lehericy S.; Letondor C.; Levy M.; Lista S.; Lowrey M.; Ly J.; Makiese O.; Masetti I.; Mendes A.; Metzinger C.; Michon A.; Mochel F.; Nait Arab R.; Nyasse F.; Perrin C.; Poirier F.; Poisson C.; Potier M.C.; Ratovohery S.; Revillon M.; Rojkova K.; Santos-Andrade K.; Schindler R.; Servera M.C.; Seux L.; Simon V.; Skovronsky D.; Thiebaut M.; Uspenskaya O.; Vlaincu M.; Aguilar L.F.; Babiloni C.; Baldacci F.; Benda N.; Black K.L.; Bokde A.L.W.; Bonuccelli U.; Broich K.; Bun R.S.; Cacciola F.; Castrillo J.; Cavedo E.; Ceravolo R.; Chiesa P.A.; Colliot O.; Coman C.M.; Corvol J.C.; Cuello A.C.; Cummings J.L.; Depypere H.; Dubois B.; Duggento A.; Durrleman S.; Escott-Price V.; Federoff H.; Ferretti M.T.; Fiandaca M.; Frank R.A.; Garaci F.; Genthon R.; George N.; Giorgi F.S.; Graziani M.; Haberkamp M.; Habert M.O.; Hampel H.; Herholz K.; Karran E.; Kim S.H.; Koronyo Y.; Koronyo-Hamaoui M.; Lamari F.; Langevin T.; Lehericy S.; Lista S.; Lorenceau J.; Mapstone M.; Neri C.; Nistico R.; Nyasse-Messene F.; O'Bryant S.E.; Perry G.; Ritchie C.; Rojkova K.; Rossi S.; Santarnecchi E.; Schneider L.S.; Sporns O.; Toschi N.; Verdooner S.R.; Vergallo A.; Villain N.; Welikovitch L.; Woodcock J.; Younesi E.Vergallo, A.; Bun, R. -S.; Toschi, N.; Baldacci, F.; Zetterberg, H.; Blennow, K.; Cavedo, E.; Lamari, F.; Habert, M. -O.; Dubois, B.; Floris, R.; Garaci, F.; Lista, S.; Hampel, H.; Audrain, C.; Auffret, A.; Bakardjian, H.; Baldacci, F.; Batrancourt, B.; Benakki, I.; Benali, H.; Bertin, H.; Bertrand, A.; Boukadida, L.; Cacciamani, F.; Causse, V.; Cavedo, E.; Cherif Touil, S.; Chiesa, P. A.; Colliot, O.; Dalla Barba, G.; Depaulis, M.; Dos Santos, A.; Dubois, B.; Dubois, M.; Epelbaum, S.; Fontaine, B.; Francisque, H.; Gagliardi, G.; Genin, A.; Genthon, R.; Glasman, P.; Gombert, F.; Habert, M. O.; Hampel, H.; Hewa, H.; Houot, M.; Jungalee, N.; Kas, A.; Kilani, M.; La Corte, V.; Le Roy, F.; Lehericy, S.; Letondor, C.; Levy, M.; Lista, S.; Lowrey, M.; Ly, J.; Makiese, O.; Masetti, I.; Mendes, A.; Metzinger, C.; Michon, A.; Mochel, F.; Nait Arab, R.; Nyasse, F.; Perrin, C.; Poirier, F.; Poisson, C.; Potier, M. C.; Ratovohery, S.; Revillon, M.; Rojkova, K.; Santos-Andrade, K.; Schindler, R.; Servera, M. C.; Seux, L.; Simon, V.; Skovronsky, D.; Thiebaut, M.; Uspenskaya, O.; Vlaincu, M.; Aguilar, L. F.; Babiloni, C.; Baldacci, F.; Benda, N.; Black, K. L.; Bokde, A. L. W.; Bonuccelli, U.; Broich, K.; Bun, R. S.; Cacciola, F.; Castrillo, J.; Cavedo, E.; Ceravolo, R.; Chiesa, P. A.; Colliot, O.; Coman, C. M.; Corvol, J. C.; Cuello, A. C.; Cummings, J. L.; Depypere, H.; Dubois, B.; Duggento, A.; Durrleman, S.; Escott-Price, V.; Federoff, H.; Ferretti, M. T.; Fiandaca, M.; Frank, R. A.; Garaci, F.; Genthon, R.; George, N.; Giorgi, F. S.; Graziani, M.; Haberkamp, M.; Habert, M. O.; Hampel, H.; Herholz, K.; Karran, E.; Kim, S. H.; Koronyo, Y.; Koronyo-Hamaoui, M.; Lamari, F.; Langevin, T.; Lehericy, S.; Lista, S.; Lorenceau, J.; Mapstone, M.; Neri, C.; Nistico, R.; Nyasse-Messene, F.; O'Bryant, S. E.; Perry, G.; Ritchie, C.; Rojkova, K.; Rossi, S.; Santarnecchi, E.; Schneider, L. S.; Sporns, O.; Toschi, N.; Verdooner, S. R.; Vergallo, A.; Villain, N.; Welikovitch, L.; Woodcock, J.; Younesi, E

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.

Contains fulltext : 71044.pdf (publisher's version ) (Closed access)We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7))

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT‐preAD study

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