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1. Potential Pathogenetic Role of Antimicrobial Peptides Carried by Extracellular Vesicles in an in vitro Psoriatic Model

Author

Capriotti L, Iuliano M, Lande R, Frasca L, Falchi M, Rosa P, Mangino G, and Romeo G

Subjects
extracellular vesicles, antimicrobial peptides, cytokines, keratinocytes, pathogenesis of psoriasis, comorbidities, Pathology, RB1-214, Therapeutics. Pharmacology, RM1-950
Abstract

Lorena Capriotti,1,* Marco Iuliano,1,* Roberto Lande,2 Loredana Frasca,2 Mario Falchi,3 Paolo Rosa,1 Giorgio Mangino,1 Giovanna Romeo1 1Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome – Polo Pontino, Latina, Italy; 2Pharmacological Research and Experimental Therapy Section, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy; 3National AIDS Center, Istituto Superiore di Sanità, Rome, Italy*These authors contributed equally to this workCorrespondence: Giorgio Mangino, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome – Polo Pontino, C.so della Repubblica, 79, Latina, 04100, Italy, Tel +39 0773 1757271, Email giorgio.mangino@uniroma1.itPurpose: Extracellular Vesicles (EVs) are a heterogeneous group of cell-derived membranous nanoparticles involved in several physiopathological processes. EVs play a crucial role in the definition of the extracellular microenvironment through the transfer of their cargo. Psoriasis is a prototypical chronic inflammatory disease characterized by several secreted mediators, among which antimicrobial peptides (AMPs) are considered pivotal in the development of the psoriatic inflammatory microenvironment. The role of EVs in the pathogenesis of psoriasis has not been elucidated yet, even if emerging evidence demonstrated that interleukin-17A (IL-17A), the psoriasis-related principal cytokine, modifies EVs release and cargo content. The aim of this work was to analyze whether, besides IL-17A, other psoriasis-related cytokines (ie, IFN-γ, TNF-α, IL-22 and IL-23) could affect EVs release and their AMPs mRNAs cargo as well as to analyze the potential biological effect due to EVs internalization by different acceptor cells.Methods: Nanoparticle tracking analysis (NTA) was performed on supernatants of HaCaT cells stimulated with IL-17A, IFN-γ, TNF-α, IL-22 or IL-23 to enumerate EVs. Real-Time RT-PCR was used for gene expression analysis in cells and EVs. Confocal microscopy and Flow cytometry were used to, respectively, study Netosis and EVs internalization.Results: IL-17A and IFN-γ increased EVs release by HaCaT cells. All the tested cytokines modulated AMPs mRNA expression in parental cells and in their respective EVs. S100A12 and hBD2 mRNAs were upregulated following IL-17A and IL-22 treatments. Interestingly, EVs derived from cytokine treated HaCaT cells induced Netosis in freshly isolated neutrophils. Upregulation of S100A12 and hBD2 mRNA was also detectable in acceptor cells incubated with EVs derived from cells treated with psoriasis-related cytokines.Conclusion: The obtained results highlighted the role of EVs in the composition of psoriasis-associated secretome and microenvironment also suggesting the EV involvement in the spreading of the disease mediators and in the possible associated comorbidities.Keywords: extracellular vesicles, antimicrobial peptides, cytokines, keratinocytes, pathogenesis of psoriasis, comorbidities

Published
2022

2. A Fecal Metabolite Signature of Impaired Fasting Glucose: Results From Two Independent Population-Based Cohorts

Author

Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., Menni C., Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., and Menni C.

Abstract

Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

Published
2023

4. Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Author

Lande, R., Palazzo, R., Gestermann, N., Jandus, C., Falchi, M., Spadaro, F., Riccieri, V., James, E. A., Butera, A., Boirivant, M., Feldmeyer, L., Surbeck, I., Di Lucca, J., Stuber, F., Spinelli, F. R., Botti, E., Marinari, B., Bianchi, L., Pica, R., Cerbelli, B., Giannakakis, K., Auteri, S. E., Daniels, I., Durrant, L. G., Horstman, S., Costanzo, A., Romero, P., Alessandri, C., Conti, F., Valesini, G., Gilliet, M., Chizzolini, C., and Frasca, L.

Published
2020
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5. The autophagic protein FYCO1 controls TNFRSF10/TRAIL receptor induced apoptosis and is inactivated by CASP8 (caspase 8)

Author

Coppola, V., Marino, Ilaria, Warnken, U., Falchi, M., Pasquini, L., Biffoni, M., De Maria Marchiano, Ruggero, Haas, Tobias Longin, Marino I., De Maria R. (ORCID:0000-0003-2255-0583), Haas T. L. (ORCID:0000-0003-2336-0263), Coppola, V., Marino, Ilaria, Warnken, U., Falchi, M., Pasquini, L., Biffoni, M., De Maria Marchiano, Ruggero, Haas, Tobias Longin, Marino I., De Maria R. (ORCID:0000-0003-2255-0583), and Haas T. L. (ORCID:0000-0003-2336-0263)

Abstract

Apoptosis is a tightly controlled cell death program executed by proteases, the so-called caspases. It plays an important role in tissue homeostasis and is often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end-directed transport of autophagic and endosomal vesicles as a molecular interaction partner of activated CASP8 (caspase 8). The absence of FYCO1 sensitized cells to basal and TNFSF10/TRAIL-induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC). Loss of FYCO1 resulted in impaired transport of TNFRSF10B/TRAIL-R2/DR5 (TNF receptor superfamily member 10b) to the lysosomes in TNFSF10/TRAIL-stimulated cells. More in detail, we show that FYCO1 interacted via its C-terminal GOLD domain with the CCZ1-MON1A complex, which is necessary for RAB7A activation and for the fusion of autophagosomal/endosomal vesicles with lysosomes. We demonstrated that FYCO1 is a novel and specific CASP8 substrate. The cleavage at aspartate 1306 resulted in the release of the C-terminal GOLD domain, inactivating FYCO1 function, and allowing for the progression of apoptosis. Furthermore, the lack of FYCO1 resulted in a stronger and prolonged formation of the TNFRSF1A/TNF-R1 signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a control mechanism that fine-tunes both apoptotic and inflammatory answers. Abbreviations: AP: affinity purification; CHX: cycloheximide; co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DISC: death-inducing signaling complex; DR: death receptors; doxy: doxycycline; GEF: guanine nucleotide exchange factor; ind: inducible; KD: knockdown; KO: knockout; MS: mass spectrometry; shRNA: short hairpin RNA; siRNA: small interfering RNA; TIP: two-step co-immunoprecipitation; WB: western blot.

Published
2023

9. Procedura tecnica di esame

Author

Martino, F., Silvestri, E., Grassi, W., Garlaschi, G., Falchi, M., Muda, A., Martino, Fabio, Silvestri, Enzo, Grassi, Walter, and Garlaschi, Giacomo

Published
2006
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10. Association analyses of rare variants identify two genes associated with refractive error

Author

Patasova, K., Haarman, A.E.G., Musolf, A.M., Mahroo, O.A., Rahi, J.S., Falchi, M., Verhoeven, V.J.M., Bailey-Wilson, J.E., Klaver, C.C.W., Duggal, P., Klein, A., Guggenheim, J.A., Hammond, C.J., Hysi, P.G., Patasova, K., Haarman, A.E.G., Musolf, A.M., Mahroo, O.A., Rahi, J.S., Falchi, M., Verhoeven, V.J.M., Bailey-Wilson, J.E., Klaver, C.C.W., Duggal, P., Klein, A., Guggenheim, J.A., Hammond, C.J., and Hysi, P.G.

Abstract

Contains fulltext : 282599.pdf (Publisher’s version ) (Open Access), PURPOSE: Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. METHODS: Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses. RESULTS: We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error. CONCLUSION: The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the o

Published
2022

17. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, Lee, Y-A, Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rueschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bonnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Custovic, A, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-Orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M-R, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Mueller-Nurasyid, M, Noethen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stoelzl, D, Strauch, K, Szwajda, A, Tenesa, A, Thompson, PJ, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C-J, and Lee, Y-A

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

18. Symptom clusters in COVID-19 : A potential clinical prediction tool from the COVID Symptom Study app

Author

Sudre, C. H., Lee, K. A., Lochlainn, M. N., Varsavsky, T., Murray, B., Graham, M. S., Menni, C., Modat, M., Bowyer, R. C. E., Nguyen, L. H., Drew, D. A., Joshi, A. D., Ma, W., Guo, C. G., Lo, C. H., Ganesh, S., Buwe, A., Pujol, J. C., du Cadet, J. L., Visconti, A., Freidin, M. B., El-Sayed Moustafa, J. S., Falchi, M., Davies, R., Gomez, M. F., Fall, Tove, Cardoso, M. J., Wolf, J., Franks, P. W., Chan, A. T., Spector, T. D., Steves, C. J., Ourselin, S., Sudre, C. H., Lee, K. A., Lochlainn, M. N., Varsavsky, T., Murray, B., Graham, M. S., Menni, C., Modat, M., Bowyer, R. C. E., Nguyen, L. H., Drew, D. A., Joshi, A. D., Ma, W., Guo, C. G., Lo, C. H., Ganesh, S., Buwe, A., Pujol, J. C., du Cadet, J. L., Visconti, A., Freidin, M. B., El-Sayed Moustafa, J. S., Falchi, M., Davies, R., Gomez, M. F., Fall, Tove, Cardoso, M. J., Wolf, J., Franks, P. W., Chan, A. T., Spector, T. D., Steves, C. J., and Ourselin, S.

Abstract

As no one symptom can predict disease severity or the need for dedicated medical support in coronavirus disease 2019 (COVID-19), we asked whether documenting symptom time series over the first few days informs outcome. Unsupervised time series clustering over symptom presentation was performed on data collected from a training dataset of completed cases enlisted early from the COVID Symptom Study Smartphone application, yielding six distinct symptom presenta- tions. Clustering was validated on an independent replication dataset between 1 and 28 May 2020. Using the first 5 days of symptom logging, the ROC-AUC (receiver operating characteristic – area under the curve) of need for respiratory sup- port was 78.8%, substantially outperforming personal characteristics alone (ROC-AUC 69.5%). Such an approach could be used to monitor at-risk patients and predict medical resource requirements days before they are required.

Published
2021
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19. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), and Lee, Y.-A. (Young-Ae)

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

20. Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells

Author

Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., De Maria R. (ORCID:0000-0003-2255-0583), Sette, Giovanni, Cicero, S. L., Blacona, G., Pierandrei, S., Bruno, Sabina Maria, Salvati, Valentina, Castelli, Andrea Giuliano, Falchi, M., Fabrizzi, B., Cimino, Giovanni, De Maria Marchiano, Ruggero, Biffoni, M., Eramo, A., Lucarelli, M., Sette G., Bruno S. M., Salvati V., Castelli G., Cimino G., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Question Cystic fibrosis (CF) is due to pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent improvements have enabled pharmacological therapy aiming at restoring mutated CFTR expression and function. CFTR "modulators"have revolutionised the CF therapeutic landscape, particularly the last approved, Trikafta. This drug combination is indicated by the United States Food and Drug Administration and very recently by the European Medicines Agency for genotypes carrying at least one copy of CFTR with the F508del pathogenic variant. However, several genotypes are not yet eligible for Trikafta treatment. Materials/patients and methods We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients. This approach, coupled to the development of AESC-derived personalised disease models, as organoids and air-liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological testing. Results and answer to the question We fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, which allowed the evaluation of the efficacy of clinically available modulators in restoring CFTR maturation and function of each patientderived "avatar"(theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. In addition, Trikafta showed its efficacy on three rare genotypes previously not eligible for treatment with modulators, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were obtained.

Published
2021

27. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability (Nature Genetics, (2018), 50, 5, (652-656), 10.1038/s41588-018-0100-5)

Author

Hysi P. G., Valdes A. M., Liu F., Furlotte N. A., Evans D. M., Bataille V., Visconti A., Hemani G., McMahon G., Ring S. M., Smith G. D., Duffy D. L., Zhu G., Gordon S. D., Medland S. E., Lin B. D., Willemsen G., Jan Hottenga J., Vuckovic D., Girotto G., Gandin I., Sala C., Concas M. P., Brumat M., Gasparini P., Toniolo D., Cocca M., Robino A., Yazar S., Hewitt A. W., Chen Y., Zeng C., Uitterlinden A. G., Ikram M. A., Hamer M. A., van Duijn C. M., Nijsten T., Mackey D. A., Falchi M., Boomsma D. I., Martin N. G., Hinds D. A., Kayser M., Spector T. D., Hysi, P. G., Valdes, A. M., Liu, F., Furlotte, N. A., Evans, D. M., Bataille, V., Visconti, A., Hemani, G., Mcmahon, G., Ring, S. M., Smith, G. D., Duffy, D. L., Zhu, G., Gordon, S. D., Medland, S. E., Lin, B. D., Willemsen, G., Jan Hottenga, J., Vuckovic, D., Girotto, G., Gandin, I., Sala, C., Concas, M. P., Brumat, M., Gasparini, P., Toniolo, D., Cocca, M., Robino, A., Yazar, S., Hewitt, A. W., Chen, Y., Zeng, C., Uitterlinden, A. G., Ikram, M. A., Hamer, M. A., van Duijn, C. M., Nijsten, T., Mackey, D. A., Falchi, M., Boomsma, D. I., Martin, N. G., Hinds, D. A., Kayser, M., and Spector, T. D.

Subjects
Publisher correction
Abstract

N/A

Published
2019

28. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Sodium-Hydrogen Exchangers, Genotype, Eczema, Gene Expression, Genetic predisposition to disease, Dual Specificity Phosphatase 1, Rare variants, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Cytokine Receptor Common beta Subunit, Skin diseases, Rare Diseases, Cardiovascular and Metabolic Diseases, Humans, Receptor, Notch4, Genome-Wide Association Study, Atopic dermatitis
Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Published
2020

29. Current tobacco smoking and risk from COVID-19: results from a population symptom app in over 2.4 million people

Author

Hopkinson, NS, Rossi, N, El-Sayed Moustafa, J, Laverty, AA, Quint, JK, Freydin, MB, Visconti, A, Murray, B, Modat, M, Ourselin, S, Small, K, Davies, R, Wolf, J, Spector, T, Steves, CJ, and Falchi, M

Abstract

Background The association between current tobacco smoking, the risk of developing COVID-19 and the severity of illness is an important information gap. Methods UK users of the COVID Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, were asked to log symptoms daily from 24th March 2020 to 23rd April 2020. Participants reporting that they did not feel physically normal were taken through a series of questions, including 14 potential COVID-19 symptoms and any hospital attendance. The main study outcome was the association between current smoking and the development of “classic” symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness. The number of concurrent COVID-19 symptoms was used as a proxy for severity. In addition, association of subcutaneous adipose tissue expression of ACE2, both the receptor for SARS-CoV-2 and a potential mediator of disease severity, with smoking status was assessed in a subset of 541 twins from the TwinsUK cohort. Results Data were available on 2,401,982 participants, mean(SD) age 43.6(15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834,437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to develop symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR[95%CI] 1.14[1.10 to 1.18]; >5 symptoms 1.29[1.26 to 1.31]; >10 symptoms 1.50[1.42 to 1.58]. Smoking was associated with reduced ACE2 expression in adipose tissue (Beta(SE)=-0.395(0.149); p=7.01×10-3). Interpretation These data are consistent with smokers having an increased risk from COVID-19. Funding Zoe provided in kind support for all aspects of building, running and supporting the app and service to all users worldwide. The study was also supported by grants from the Wellcome Trust, UK Research and Innovation and British Heart Foundation.

Published
2020

30. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

31. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH Study Group IBD Investigators Essen-Heidelberg Investigators AMFS Investigators MelaNostrum Consortium

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

35. A reference map of potential determinants for the human serum metabolome

Author

Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., consortium, The IMI DIRECT, Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., and consortium, The IMI DIRECT

Abstract

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites., QC 20211001

Published
2020
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36. Diagnostic value of cutaneous manifestation of SARS‐CoV‐2 infection*

Author

Visconti, A., primary, Bataille, V., additional, Rossi, N., additional, Kluk, J., additional, Murphy, R., additional, Puig, S., additional, Nambi, R., additional, Bowyer, R. C. E., additional, Murray, B., additional, Bournot, A., additional, Wolf, J., additional, Ourselin, S., additional, Steves, C. J., additional, Spector, T. D., additional, and Falchi, M., additional

Published
2021
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39. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Walters, R. G., Jacquemont, S., Valsesia, A., de Smith, A. J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., Delobel, B., Stutzmann, F., El-Sayed Moustafa, J. S., Chèvre, J.-C., Lecoeur, C., Vatin, V., Bouquillon, S., Buxton, J. L., Boute, O., Holder-Espinasse, M., Cuisset, J.-M., Lemaitre, M.-P., Ambresin, A.-E., Brioschi, A., Gaillard, M., Giusti, V., Fellmann, F., Ferrarini, A., Hadjikhani, N., Campion, D., Guilmatre, A., Goldenberg, A., Calmels, N., Mandel, J.-L., Le Caignec, C., David, A., Isidor, B., Cordier, M.-P., Dupuis-Girod, S., Labalme, A., Sanlaville, D., Béri-Dexheimer, M., Jonveaux, P., Leheup, B., Õunap, K., Bochukova, E. G., Henning, E., Keogh, J., Ellis, R. J., MacDermot, K. D., van Haelst, M. M., Vincent-Delorme, C., Plessis, G., Touraine, R., Philippe, A., Malan, V., Mathieu-Dramard, M., Chiesa, J., Blaumeiser, B., Kooy, R. F., Caiazzo, R., Pigeyre, M., Balkau, B., Sladek, R., Bergmann, S., Mooser, V., Waterworth, D., Reymond, A., Vollenweider, P., Waeber, G., Kurg, A., Palta, P., Esko, T., Metspalu, A., Nelis, M., Elliott, P., Hartikainen, A.-L., McCarthy, M. I., Peltonen, L., Carlsson, L., Jacobson, P., Sjöström, L., Huang, N., Hurles, M. E., OʼRahilly, S., Farooqi, I. S., Männik, K., Jarvelin, M.-R., Pattou, F., Meyre, D., Walley, A. J., Coin, L. J. M., Blakemore, A. I. F., Froguel, P., and Beckmann, J. S.

Published
2010
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42. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author

Duffy, D.L., Zhu, G., Li, X., Sanna, M., Iles, M.M., Jacobs, L.C., Evans, D.M., Yazar, S., Beesley, J., Law, M.H., Kraft, P., Visconti, A., Taylor, J.C., Liu, F., Wright, M.J., Henders, A.K., Bowdler, L., Glass, D., Ikram, M.A., Uitterlinden, A.G., Madden, P.A., Heath, A.C., Nelson, E.C., Green, A.C., Chanock, S., Barrett, J.H., Brown, M.A., Hayward, N.K., MacGregor, S., Sturm, R.A., Hewitt, A.W., Kayser, M., Hunter, D.J., Bishop, J.A.N., Spector, T.D., Montgomery, G.W., Mackey, D.A., Smith, G.D., Nijsten, T.E., Bishop, D.T., Bataille, V., Falchi, M., Han, J., Martin, N.G., Lee, J.E., Brossard, M., Moses, E.K., Song, F., Kumar, R., Easton, D.F., Pharoah, P.D.P., Swerdlow, A.J., Kypreou, K.P., Harland, M., Randerson-Moor, J., Akslen, L.A., Andresen, P.A., Avril, M.F., Azizi, E., Scarra, G.B., Brown, K.M., Debniak, T., Elder, D.E., Fang, S.Y., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E.M., Goldstein, A.M., Gruis, N.A., Hansson, J., Helsing, P., Hocevar, M., Hoiom, V., Ingvar, C., Kanetsky, P.A., Chen, W.V., Landi, M.T., Lang, J., Lathrop, G.M., Lubinski, J., Mackie, R.M., Mann, G.J., Molven, A., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J.A., Radford-Smith, G.L., Stoep, N. van der, Doorn, R. van, Whiteman, D.C., Craig, J.E., Schadendorf, D., Simms, L.A., Burdon, K.P., Nyholt, D.R., Pooley, K.A., Orr, N., Stratigos, A.J., Cust, A.E., Ward, S.V., Schulze, H.J., Dunning, A.M., Demenais, F., Amos, C.I., and Melanoma GWAS Consortium

Published
2019

43. The 3rd annual congress of the European society of skeletal radiology

Author

Bloem, J. L., Geirnaerdt, M. J. A., Hogendoorn, P. C. W., Chevrot, A., Davies, A. M., Hájek, M., Kurková, D., Herynek, V., Imhof, H., Masciocchi, C., Maffey, M. V., Møller, J. F., Putz, R., Reiser, M. F., Braunschweig, R., Bonél, H., Stäbler, A., Watt, I., Adams, J. E., Harake, M. D. J., Lipscomp, K., Selby, P. L., Aparisi, F., Arana, E., Lloret, R. M., Marti-Bonmati, I., Menor, F., Sanchez, E., Rodrigo, C., Beltran, J., Cifrian, C., Garci, J. L., Memis, A., Arkun, R., Akalin, T., Ustu, E. E., Sabah, D., Barile, A., Rossi, F., Zugaro, L., Manetta, R., Maurizi Enrici, R., Beggs, I., Bianchi, S., Martinoli, C., Molini, L., Gandolfo, N., Damiani, S., Helmberger, T., Sittek, H., Steinborn, M., Ritter, M. M., Geisst, H. C., Pistitsch, C., Herrmann, K., Bögl, K., Kainberger, F., Adlassnig, K. P., Kolousek, G., Leitich, H., Kolarz, G., Bracke, P., Ramon, F., Stevens, W., De Clarck, L., De Schepper, A., Sys, J., Michielsen, J., Martens, M., Breitenseher, M. J., Trattnig, S., Gaebler, C., Metz, V., Kukla, C., Gneger, A., Rand, T., Brossmann, J., Andresen, R., Preidler, K. W., Daenen, B., DeMaeseneer, M., Resnick, D., Burnett, S., Saifuddin, A., White, J., Cassar-Pullicino, V. N., Inman, C., Griffiths, J., McCall, I. W., Masri, W. E., Csókási, Z., Forgacs, S., Czerny, C., Neuhold, A., Hofmann, S., Tschauner, C., Engel, A., Recht, M. P., Kramer, J., DeBeuckeleer, L., DeSchepper, A., Somerville, J., Vandevenne, J., De Maeseneer, M., Jaovishidha, S., Sartoris, D. J., Elizagaray, E., Saez, F., Faletti, C., De Stefano, N., Sorrentin, T., Foderà Pierangeli, L., Mona, D., Foster, J. E., Taberner, J., Keen, M., Dieppe, P., Freyschmidt, J., Gibbon, W. W., O'Connor, P. J., McGonagle, D., Emery, P., Grampp, S., Lang, P., Jergas, M., Glüer, C. C., Steiner, E., Takada, M., Mathur, A., Genant, H. K., Jevtic, V., Rozman, B., Kos-Golja, M., Demsar, F., Nehrer, S., Seidl, G., Baldt, M., Klarlund, M., Østergaard, M., Sørensen, K., Lorenzen, I., Eschberger, J., Gstettner, M., Schneider, W., Plenk, H., Kühne, J. H., Steinborn, A., Dürr, H. R., Scheidler, J., Lienemann, A., Landsiedl, F., Mamdorff, P., Honda, G., Rosenau, W., Johnston, J., Mindell, E., Peterfy, C. G., Nevitt, M., Majumdar, S., Lecouvet, F. E., Vande Berg, B. C., Maighem, J., Michaux, J. L., Maldague, B. E., Lecoevet, F. E., Malghem, J., Mastantuono, M., Larciprete, M., Bassetti, E., Argento, G., Amoroso, M., Satragno, L., Nucci, F., Romanini, L., Passariello, R., McNally, E. G., Goodman, T. R., Merkle, E. M., Krammel, E., Vogel, J., Krämer, S., Schulte, M., Usadel, S., Kern, P., Brambs, H. J., Mester, Á., Makó, E., Papp, E., Kiss, K., Márton, E., Dévai, T., Duffek, L., Bártfai, K., Németh, L., Karlinger, K., Posgay, M., Kákosy, T., Davies, G. A., Cowen, A. R., Fowler, R. C., Bury, R. F., Parkin, G. J. S., Lintott, D. J., Martinez, D., Safadin, A., Pal, C. R., Ostlere, S. J., Phillps, A. J., Athanasou, N., Lemperle, S. M., Holmes, R. E., Rühm, S., Zanetti, M., Romero, J., Hodler, J., Larena, J. A., Marti-Bonmarti, L., Martin, I., Tabernero, G., Alonso, A., Scarabino, T., Guglielmi, G., Giannatempo, G. M., Cammisa, M., Salvolini, U., Schmitt, R., Fellner, F., Heinze, A., Obletter, N., Schnarkowski, P., Tirman, P. F. J., Steinbach, L. S., Schneider, P., Ferrettiz, J. L., Capozza, R. F., Braun, M., Reiners, C., Zettl, R., Silvestri, E., Falchi, M., Delucchi, S., Cella, R., Neumaier, C. E., Prato, N., Migliorini, S., Jessel, C., Heuck, A., Stevens, K. J., Preston, B. J., Kerslake, R. W., Wright, W., Wallace, W. A., Stiskal, M., Szolar, D., Stenzel, I., Mesaric, P., Smolen, J., Czembirek, H., Tasker, A. D., Benson, M. K., Fleischmann, D., Haller, J., Rottmann, B., Kontaxis, G., Vanel, D., Missenard, G., Le Cesne, A., Guinebretiere, J. M., Verhoek, G., Duewell, S., Zollinger, H., Vrooman, H. A., Valstar, E. R., Brand, G. J., Obermann, W. R., Rozing, P. M., Reiber, J. H. C., Zafiroski, G., Kamnar, J., Zografski, G., Jeftic, V., Vidoevski, G., Ledermann, T., Zerbi, A., Gambaretti, R., Trenti, N., Zanolla, W., Allen, A. W., Willis, Ch. E., Radmer, S., Hakim, S., Banzer, D., Sparmann, M., Argent, J. D., Sampson, M. A., Baur, A., Bartl, R., Llopis, E., Monton, T., Vallcanera, A., Serafini, G., Bertolotto, M., Trudell, D., White, L. M., Garlaschi, G., DiLella, G. M., Bray, A., Parrella, A., Salvia, F., Parrella, R. E., Esztergályos, J., Faul, S., Link, J., Behrendt, S., Helbich, T., Steingruber, I., Gahleitner, A., Kettenbach, J., Kreuzer, S., Lomoschitz, F., Kaposi, P. N., Reti, P. G., Kolenc, M., Turk, Z., Barovic, J., Kugler, Ch., Uggowitzer, M., Gröll, R., Raith, J., Ranner, G., Liskutin, J., Youssefzadeh, S., Montagnon, C., Billiard, J. S., Tanji, P., Peerally, S., Gazielly, D., Muhaz-Vives, J. M., Fernández, J., Girveni-Montilos, R., Catasuz-Capellades, X., Valls-Pascual, R., Niitsu, M., Mishima, H., Itai, Y., Pirronti, T., Sallustio, G., Cerase, A., Priolo, F., Poleksic, L., Atanackovic, M., Dimitrijevic, B., Bacic, G., Potsybina, V. V., Rangger, Ch., Kathrein, A., Klestil, T., Gabl, M., Daniaux, H., Recondo, J. A., Alustiza, J. M., Villanua, J., Barrera, M. C., Salvador, E., Larrea, J. A., and Martin, J.

Published
1996
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45. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, Amos, CI, Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, Lee, JE, Brossard, M, Moses, EK, Song, F, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Schulze, H-J, Dunning, AM, Demenais, F, and Amos, CI

Abstract

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Published
2019

46. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

Author

Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., De Maria R. (ORCID:0000-0003-2255-0583), Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.

Published
2019

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