Search

Your search keyword '"Gallo M"' showing total 303 results
Start Over Author "Gallo M" Language undetermined
303 results on '"Gallo M"'

1. Optimizing product assortment, joint replenishments, and storage capacity allocation in a deteriorating inventory system

Author

Castellano D., Gallo M., Grassi A., Santillo L. C., Castellano, D., Gallo, M., Grassi, A., and Santillo, L. C.

Subjects
Optimization, Control and Systems Engineering, Inventory, Joint replenishment, Capacity allocation, Decay, Assortment
Abstract

In this paper, we consider a single retailer who sells multiple products subject to decay, and that implements coordinated inventory replenishments among them. The overall available surface at the retailer is limited and is partitioned into two areas: the backroom facility and the display area. The demand rate of each product is a function of displayed quantity and location, and it also depends on the cross-elasticity among items. The objective is to find the product assortment, the replenishment policy of each product, the quantity to be displayed, and the surfaces assigned to the backroom and display areas that maximize the total profit per time unit. We develop the mathematical model and formulate the optimization problem. Finally, we investigate the model response by means of numerical experiments considering several problem instances. Copyright © 2022 IFAC.

Published
2022

2. Aircraft Hybrid-Electric Propulsion: Development Trends, Challenges and Opportunities

Author

Josselyn Gallo M., Manuel A. Rendon, Carlos D. Sánchez R., and Alexandre H. Anzai

Subjects
Engineering, Service (systems architecture), business.industry, Energy management, Energy Engineering and Power Technology, ComputerApplications_COMPUTERSINOTHERSYSTEMS, Hybrid-electric propulsion, Propulsion, Article, Energy storage, Computer Science Applications, Supply and demand, Electrically powered spacecraft propulsion, Work (electrical), Control and Systems Engineering, Power electronics, Systems engineering, Electrical and Electronic Engineering, Architecture, business, Electric energy storage
Abstract

The present work is a survey on aircraft hybrid electric propulsion (HEP) that aims to present state-of-the-art technologies and future tendencies in the following areas: air transport market, hybrid demonstrators, HEP topologies applications, aircraft design, electrical systems for aircraft, energy storage, aircraft internal combustion engines, and management and control strategies. Several changes on aircraft propulsion will occur in the next 30 years, following the aircraft market demand and environmental regulations. Two commercial areas are in evolution, electrical urban air mobility (UAM) and hybrid-electric regional aircraft. The first one is expected to come into service in the next 10 years with small devices. The last one will gradually come into service, starting with small aircraft according to developments in energy storage, fuel cells, aircraft design and hybrid architectures integration. All-electric architecture seems to be more adapted to UAM. Turbo-electric hybrid architecture combined with distributed propulsion and boundary layer ingestion seems to have more success for regional aircraft, attaining environmental goals for 2030 and 2050. Computational models supported by powerful simulation tools will be a key to support research and aircraft HEP design in the coming years. Brazilian research in these challenging areas is in the beginning, and a multidisciplinary collaboration will be critical for success in the next few years.

Published
2021

3. Molecular typing and genome sequencing allow the identification of persistent Listeria monocytogenes strains and the tracking of the contamination source in food environments

Author

Lucchini, R, Carraro, L, Pauletto, M, Gallo, M, Andreani, N A, Weiss, G, Tessaro, C, Babbucci, M, and Cardazzo, B

Subjects
Strain traceability in food processing facilities, Strain persistence, General Medicine, SNP analysis, WGS of lm genomes, 2b-RAD typing, Listeria monocytogenes, Microbiology, Food Science
Abstract

The presence of Listeria monocytogenes (Lm) in the food processing environment (facilities and products) is a challenging problem in food safety management. Lm is one of the main causes of mortality in foodborne infections, and the trend is continuously increasing. In this study, a collection of 323 Lm strain isolates recovered from food matrices and food industry environments (surfaces and equipment) over four years from 80 food processing facilities was screened using a restriction site-associated tag sequencing (2b-RAD) typing approach developed for Lm. Thirty-six different restriction site-associated DNA (RAD) types (RTs) were identified, most of which correspond to lineage II. RT1, the most represented genotype in our collection and already reported as one of the most prevalent genotypes in the food environment, was significantly associated with meat processing facilities. The sequencing of the genomes of strains belonging to the same RT and isolated in the same facility in different years revealed several clusters of persistence. The definition of the persistent strains (PSs) allowed the identification of the potential source of contamination in the incoming raw meat that is introduced in the facility to be processed. The slaughterhouses, which, according to the European Union (EU) regulation, are not inspected for the presence of Lm could be hotspots for the persistence of Lm PSs.

Published
2022

18. Open issues on G3 neuroendocrine neoplasms: back to the future

Author

Zatelli, Maria Chiara, Guadagno, Elia, Messina, Erika, Lo Calzo, Fabio, Faggiano, Antongiulio, Colao, Annamaria, Albertelli, M., Bianchi, A., CIRCELLI, MARIA TERESA, De Cicco, F., Dicitore, A., Di Dato, C., MOLFETTA, MARIA TERESA, Fanciulli, G., Ferraù, F., Gallo, M., GIANNETTA, MASSIMO, Grillo, F., Grossrubatscher, E., Guarnotta, V., Isidori, A. M., Kara, E., MALANDRINO, CORRADO, Modica, R., Muscogiuri, G., Pizza, G., Razzore, P., Rota, F., Rubino, M., Ruggeri, R. M., Sciammarella, C., Vitale, G., Zatelli, Maria Chiara, Guadagno, Elia, Messina, Erika, Lo Calzo, Fabio, Faggiano, Antongiulio, Colao, Annamaria, Albertelli, M., Bianchi, A., Circelli, MARIA TERESA, De Cicco, F., Dicitore, A., Di Dato, C., Molfetta, MARIA TERESA, Fanciulli, G., Ferraù, F., Gallo, M., Giannetta, Massimo, Grillo, F., Grossrubatscher, E., Guarnotta, V., Isidori, A. M., Kara, E., Malandrino, Corrado, Modica, R., Muscogiuri, G., Pizza, G., Razzore, P., Rota, F., Rubino, M., Ruggeri, R. M., Sciammarella, C., and Vitale, G.

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Prognosi, Endocrinology, Diabetes and Metabolism, Neuroendocrine tumors, Diagnosis, G3, neuroendocrine tumors, prognosis, endocrinology, diabetes and metabolism, oncology, cancer research, NO, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Neuroendocrine tumor, medicine, Humans, Prognosis, Oncology, Intensive care medicine, business.industry, medicine.disease, Neuroendocrine Carcinomas, Diabetes and Metabolism, 030104 developmental biology, 030220 oncology & carcinogenesis, Neoplasm Grading, business, Diagnosi
Abstract

The recent recognition that grade 3 (G3) neuroendocrine neoplasms (NENs) can be divided into two different categories according to the histopathological differentiation, that is G3 neuroendocrine tumors (NETs) and G3 neuroendocrine carcinomas (NECs) has generated a lot of interest concerning not only the diagnosis, but also the differential management of such new group of NENs. However, several issues need to be fully clarified in order to put G3 NETs and G3 NECs in the right place. The aim of this review is to focus on those issues that are still undetermined starting from the current knowledge, evaluating the available evidence and the possible clinical implications.

Published
2018

19. Parental Nativity and Familial Acceptance of Sexual and Gender Minority Latinx Youth

Author

Pineiro T, Simons J, and Gallo M

Subjects
Psychology, Developmental psychology
Abstract

Accepting and sharing about oneself as a sexual and gender minority (SGM) individual is complex. This is even more complex for individuals who identify as both SGM and Latino because they possess more than one minoritized identity. As a result, SGM Latino youth are more susceptible to higher levels of stress, which if not effectively managed, can lead to homelessness, anxiety and depression, and substance abuse. Latino family members find it difficult to learn how to positively interact with their SGM family member (e.g., in the early phases of coming out). In this quantitative survey study, researchers examined survey data collected from 1,877 Latino youth concerning home experiences, health, identity, and parental nativity. Data were drawn from the LGBTQ National Teen Survey, an online, anonymous comprehensive survey designed to advance understanding of the experiences of SGM adolescents (13-17 years of age). The survey, developed and distributed by the Human Rights Campaign, examined perceptions of familial acceptance regarding SGM identity during youth. Significant relationships were found between family acceptance, sexual orientation, and parental nativity (birthplace of parents in- or outside of the United States). The findings provide for a rich discussion about the implications for helping Latino SGM youth and educating Latino family members.

Published
2021

20. Gut IgA Enhances Systemic IgG Responses to Pneumococcal Vaccines Through the Commensal Microbiota

Author

García Prat M, Charlotte Cunningham-Rundles, Emilie K. Grasset, Giuliana Magri, Cindy Gutzeit, Paul J. Maglione, Pybus M, Martín Nalda A, Dieli-Crimi R, Lewis Tomalin, Tejedor Vaquero S, Tachó-Piñot R, Graham J. Britton, Martinez Gallo M, Suarez-Farina M, Andrea Cerutti, Saurabh Mehandru, Jose C. Clemente, Veeramreddy Pk, Jeremiah J. Faith, and Dean B. Matthews

Subjects
T cell, Chromosomal translocation, Biology, Gut flora, biology.organism_classification, Immunoglobulin G, medicine.anatomical_structure, Immune system, Antigen, Immunology, medicine, biology.protein, Receptor, B cell
Abstract

SUMMARYThe gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.

Published
2021

21. Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks

Author

Fanciulli G., Di Molfetta S., Dotto A., Florio T., Feola T., Rubino M., de Cicco F., Colao A., Faggiano A., Albertelli M., Altieri B., Barrea L., Bottiglieri F., Campione S., Dicitore A., Ferone D., Ferrau F., Grossrubatscher E., Gallo M., Giannetta E., Grillo F., Guadagno E., Guarnotta V., Isidori A. M., Lania A., Lenzi A., Lo Calzo F., Malandrino P., Messina E., Modica R., Muscogiuri G., Pizza G., Pes L., Pofi R., Puliani G., Rainone C., Razzore P., Rizza L., Ruggieri R. M., Sbardella E., Sesti F., Venneri M. A., Vitale G., Zatelli M. C., Fanciulli G., Di Molfetta S., Dotto A., Florio T., Feola T., Rubino M., de Cicco F., Colao A., Faggiano A., Albertelli M., Altieri B., Barrea L., Bottiglieri F., Campione S., Dicitore A., Ferone D., Ferrau F., Grossrubatscher E., Gallo M., Giannetta E., Grillo F., Guadagno E., Guarnotta V., Isidori A.M., Lania A., Lenzi A., Lo Calzo F., Malandrino P., Messina E., Modica R., Muscogiuri G., Pizza G., Pes L., Pofi R., Puliani G., Rainone C., Razzore P., Rizza L., Ruggieri R.M., Sbardella E., Sesti F., Venneri M.A., Vitale G., Zatelli M.C., Fanciulli, G., Di Molfetta, S., Dotto, A., Florio, T., Feola, T., Rubino, M., de Cicco, F., Colao, A., Faggiano, A., Albertelli, M., Altieri, B., Barrea, L., Bottiglieri, F., Campione, S., Dicitore, A., Ferone, D., Ferrau, F., Grossrubatscher, E., Gallo, M., Giannetta, E., Grillo, F., Guadagno, E., Guarnotta, V., Isidori, A. M., Lania, A., Lenzi, A., Lo Calzo, F., Malandrino, P., Messina, E., Modica, R., Muscogiuri, G., Pizza, G., Pes, L., Pofi, R., Puliani, G., Rainone, C., Razzore, P., Rizza, L., Ruggieri, R. M., Sbardella, E., Sesti, F., Venneri, M. A., Vitale, G., and Zatelli, M. C.

Subjects
atezolizumab, avelumab, cemiplimab, durvalumab, immune checkpoint inhibitors, ipilimumab, nivolumab, paraganglioma, pembrolizumab, pheochromocytoma, lcsh:Medicine, Ipilimumab, Review, Immune checkpoint inhibitor, Pembrolizumab, Bioinformatics, Pheochromocytoma, Avelumab, 03 medical and health sciences, 0302 clinical medicine, Paraganglioma, Atezolizumab, Medicine, Ate-zolizumab, 030304 developmental biology, 0303 health sciences, business.industry, lcsh:R, General Medicine, medicine.disease, Clinical trial, 030220 oncology & carcinogenesis, Nivolumab, business, medicine.drug
Abstract

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respectively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progressive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology.

Published
2020

22. SOFC In-Field Test of a Tool for Advanced Monitoring, Diagnostics and Lifetime Prognostics

Author

Ouweltjes, J.P., Gallo, M., Polverino, P., Galiano, F., Pofahl, S.N., Boškoski, P., Nusev, G., Caliandro, P., and Leonardi, A.

Subjects
EFCF2020, SOx
Abstract

Accurate state-of-health (SoH) monitoring is considered a key element in avoiding faulty operation of fuel cell stacks. Such faulty operation could relate to problems in the balanceof-plant, having a global effect on the stack performance, or to problems in the stack itself, where the effect could initially be very local. This research topic was addressed in the European project INSIGHT, with the final aim to demonstrate advanced SoH monitoring in a real environment by implementing newly developed hardware equipped with novel perturbation routines and data fitting routines in a µ-CHP system from SOLIDpower. The results of the test that followed, including validation of the routines and hardware as well as simulation of different kinds of faulty operation, are reported here.

Published
2021
Full Text
View/download PDF

25. The effect of oxygen ions on the stability and polarization of Kinetic Alfv��n Waves in the Magnetosphere

Author

Moya, Pablo S., Gallo-M��ndez, Iv��n, and Zenteno-Quinteros, Bea

Subjects
Plasma Physics (physics.plasm-ph), Physics::Plasma Physics, Physics::Space Physics, FOS: Physical sciences, Space Physics (physics.space-ph)
Abstract

One of the most striking properties of Kinetic Alfv��n Waves (KAW) is that, unlike the also Alfv��nic Electromagnetic Ion Cyclotron (EMIC) waves, these waves are right-hand polarized in the plasma frame. In particular, this signature property is key for the identification of KAW from in situ measurements of plasma waves. From the theoretical point of view, both the dispersion relation and the polarization of KAW has been mostly studied in proton-electron plasmas. However, most astrophysical and space plasmas are multi-species, and therefore in these systems the dispersion properties of the KAW may not depend only on the macroscopic parameters of proton and electron distributions, but also on the parameters of heavier ions. Here, using Vlasov linear theory we study the dispersion properties of Alfv��nic modes in multi-species plasmas composed by electrons, protons, and O$^+$ ions, with macroscopic plasma parameters relevant to the inner magnetosphere. In consistency with recent observations, our numerical results show that the presence of O$^+$ ions allows the existence of KAW in a wider wave-number range and at smaller wave-normal angles compared to the electron-proton case, but at the same time isotropic O$^+$ ions tend to reduce (or even inhibiting) the growth rates of unstable KAW triggered by anisotropic protons. These results suggest that magnetospheric ions may play an important role on the energy transfer from large macroscopic scales to sub-ionic and electronic scales, especially during intense geomagnetic storms in which O$^+$ ions can dominate the plasma composition in the inner magnetosphere., 16 pages, 4 figures, in press

Published
2021
Full Text
View/download PDF

27. Coordinated Response to Imported Vaccine-Derived Poliovirus Infection, Barcelona, Spain, 2019-2020

Author

Álamo-Junquera, Dolores, Politi, Julieta, Simón, Pere, Dieli-Crimi, Romina, Borrell, Ricardo Pujol, Colobrán Oriol, Roger, Martínez-Gallo, M., Campins Martí, Magda, Antón, Andrés, Esperalba, Juliana, Andrés, Cristina, Codina, María Gema, Polverino, E., Rosa Narciso, M., Molinero, Emilia, Rius i Gibert, Maria Cristina, and Universitat Autònoma de Barcelona

Subjects
Barcelona, Microbiology (medical), Acute flaccid paralysis, medicine.medical_specialty, complications, Epidemiology, 030231 tropical medicine, Infectious and parasitic diseases, RC109-216, medicine.disease_cause, oral, 03 medical and health sciences, 0302 clinical medicine, immunologic deficiency syndromes, medicine, Humans, viruses, 030212 general & internal medicine, Disease Eradication, Adverse effect, business.industry, Public health, Poliovirus, Common variable immunodeficiency, Dispatch, vaccines, Coordinated Response to Imported Vaccine-Derived Poliovirus Infection, Barcelona, Spain, 2019–2020, medicine.disease, Virology, vaccine-preventable diseases, Infectious Diseases, Spain, poliovirus vaccine, Poliovirus Vaccine, Oral, surveillance, adverse effects, Medicine, disease eradication, Vaccine-preventable diseases, Vaccine derived poliovirus, business, Poliomyelitis
Abstract

In 2019, the Public Health Agency of Barcelona, Spain, was notifi ed of a vaccine-derived poliovirus infection. The patient had an underlying common variable immunodefi ciency and no signs of acute fl accid paralysis. We describe the ongoing coordinated response to contain the infection, which included compassionate-use treatment with pocapavir.

Published
2021

28. Expected and paradoxical effects of obesity on cancer treatment response

Author

Gallo, M, Adinolfi, V, Barucca, V, Prinzi, N, Renzelli, V, Barrea, L, Di Giacinto, P, Ruggeri, Rm, Sesti, F, Arvat, E, Baldelli, R, Eolo, Group, Colao, A, Isidori, A, Lenzi, A, Baldell, R, Albertelli, M, Attala, D, Bianchi, A, Di Sarno, A, Feola, T, Mazziotti, G, Nervo, A, Pozza, C, Puliani, G, Razzore, P, Ramponi, S, Ricciardi, S, Rizza, L, Rota, F, Sbardella, E, and Zatelli, Mc.

Subjects
Oncology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, body mass index, cancer, cancer therapy, obesity, overweight, treatment outcome, Overweight, NO, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Risk Factors, Internal medicine, Diabetes mellitus, Neoplasms, Epidemiology, medicine, Humans, Cancer, Obesity, Body mass index, Cancer therapy, Treatment outcome, LS4_3, Risk factor, business.industry, medicine.disease, Prognosis, Cardiovascular Diseases, medicine.symptom, business, Obesity paradox
Abstract

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Published
2020

29. 50 años del Programa de Cribado Neonatal en Cataluña

Author

Marín Soria JL, López Galera RM, Argudo Ramírez A, González de Aledo JM, Pajares García S, Navarro Sastre A, Hernandez Pérez JM, Ribes Rubio A, Gort Mas L, García Villoria J, Gartner Tizano S, Rovira Amigo S, Asensio de la Cruz O, García González M, Cols M, Costa-Colomer J, Bádenas Orquin C, Yeste Fernández D, Campos Martorell A, Clemente León M, Mogas Viñals E, Ferrer Costa R, Giralt Arnaiz M, Campistol-Plana J, Garcia-Cazorla A, Beneitez Pastor D, Ortuño Cabrero A, Blanco Álvarez A, Tazón Vega B, Roué G, Velasco Puyo P, Murciano Carrillo T, Murillo Sanjuan L, Díaz de Heredia Rubio C, Mañú Pereira MDM, Vives Corrons JL, Arranz Amo JA, Carnicer Cáceres C, Del Toro Riera M, Ormazábal Herrero A, Artuch-Iriberri R, García-Volpe C, de los Santos MM, Sierra-March C, Ruiz-Hernández CJ, Meavilla-Olivas SM, Martín Nalda A, Rivière JG, Parra Martínez A, Soler Palacín P, Martínez Gallo M, Colobran R, Casals Senent T, Armelles Sebastia M, Vidal Benede MJ, Jané Checa M, Fernández Bordón RM, Asso Ministral L, Prats Viedma B, and Cabezas Peña C

Subjects
Congenital hypothyroidism, 50th anniversary, Catalonia, Severe combined immunodeficiency, Spain, Sickle cell disease, Phenylketonuria, Inborn errors of metabolism, Cystic fibrosis, Newborn Screening, Universal
Abstract

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.

Published
2020

30. Molecular analysis of the novel L243R mutation in STXBP2 reveals impairment of degranulation activity

Author

Viñas-Giménez L, Donadeu L, Alsina L, Rincón R, de la Campa EÁ, Esteve-Sole A, Català-Temprano A, Colobran R, de la Cruz X, Sayós J, and Martínez-Gallo M

Subjects
Cytotoxic T-lymphocytes, Familial hemophagocytic lymphohistiocytosis, Epstein–Barr virus infection, Natural killer cells, Munc18-2 protein, Munc18-1 protein, Cell degranulation
Abstract

The presence of mutations in PRF1, UNC13D, STX11 and STXBP2 genes in homozygosis or compound heterozygosis results in immune deregulation. Most such cases lead to clinical manifestations of haemophagocytic lymphohistiocytosis (HLH). In the present study, we analyzed degranulation and cytotoxicity in a pediatric patient with a late presentation of HLH associated with Epstein-Barr virus infection. Remarkably, the results of the degranulation assay showed reduction of CD107a median fluorescence intensity (MFI) and absent cytotoxicity. Genetic analysis identified compound heterozygous mutations in STXBP2 gene: a previously reported splicing defect in exon 15 (c.1247-1G>C, p.V417LfsX126) and a novel missense mutation in exon 9 (c.728T>G, p.L243R). Transfection experiments of STXBP2-L243R or STXBP2-WT constructs showed an undetectable protein expression of the STXBP2-L243R mutation. The residue L243 is highly preserved evolutionarily; moreover, computational analysis of its structure revealed its participation in the rich network of interactions that stabilizes domains 2 and 3 of the protein. Altogether, we demonstrated by molecular and in silico analysis that the new L243R mutation in STXBP2 plays a pathogenic role that, together with the p.Val417Leufsc mutation, shows the synergistic negative effect of these two mutations on STXBP2 function, leading to a decrease of degranulatory activity in vivo.

Published
2020

31. Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Author

Zatelli, Maria Chiara, Fanciulli, Giuseppe, Malandrino, Pasqualino, NIKE GROUP: Albertelli M, Arvat E, Baldelli R, Berruti A, Bianchi A, Bodei L, Botti G, Corcione F, Daví MV, Delle Fave G, De Marinis L, Di Sarno A, Dicitore A, Fazio N, Ferolla P, Ferone D, Filice A, Gallo M, Giordano C, Giuffrida D, Guarnotta V, Lania A, Lastoria S, Logoluso F, Loli P, Manzoni M, Marchetti M, Martini C, Messina E, Modica R, Motta C, Papotti M, Partelli S, Persico G, Pia A, Piovesan A, Pontecorvi A, Razzore P, Rota F, Scavuzzo F, Sciammarella C, Vitale G., RAMUNDO, VALERIA, FAGGIANO, ANTONGIULIO, COLAO, ANNAMARIA, DE ROSA, GAETANO, Zatelli, M, Fanciulli, G, Malandrino, P, Ramundo, V, Faggiano, A, Colao, A, Giordano, C, Zatelli, Mc, Nike, Group, Partelli, S, Zatelli, Maria Chiara, Fanciulli, Giuseppe, Malandrino, Pasqualino, Ramundo, Valeria, Faggiano, Antongiulio, Colao, Annamaria, NIKE GROUP: Albertelli, M, Arvat, E, Baldelli, R, Berruti, A, Bianchi, A, Bodei, L, Botti, G, Corcione, F, Daví, Mv, Delle Fave, G, De Marinis, L, DE ROSA, Gaetano, Di Sarno, A, Dicitore, A, Fazio, N, Ferolla, P, Ferone, D, Filice, A, Gallo, M, Giuffrida, D, Guarnotta, V, Lania, A, Lastoria, S, Logoluso, F, Loli, P, Manzoni, M, Marchetti, M, Martini, C, Messina, E, Modica, R, Motta, C, Papotti, M, Persico, G, Pia, A, Piovesan, A, Pontecorvi, A, Razzore, P, Rota, F, Scavuzzo, F, Sciammarella, C, and Vitale, G.

Subjects
0301 basic medicine, Oncology, Cancer Research, mTOR inhibitor, Endocrinology, Diabetes and Metabolism, Neuroendocrine tumors, Antineoplastic Agent, 0302 clinical medicine, Endocrinology, Neuroendocrine tumours, neuroendocrine tumour, Treatment resistance, MTOR inhibitors, Tumor, Medical treatment, TOR Serine-Threonine Kinases, Discovery and development of mTOR inhibitors, Response to treatment, Patient management, Diabetes and Metabolism, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Neuroendocrine Tumor, Human, Predictors, Animals, Antineoplastic Agents, Biomarkers, Tumor, Diagnostic Imaging, Humans, Protein Kinase Inhibitors, medicine.medical_specialty, Protein Kinase Inhibitor, Early detection, predictor, Biology, NO, 03 medical and health sciences, mTOR inhibitors, neuroendocrine tumours, predictors, response to treatment, Internal medicine, medicine, mTOR inhibitors,neuroendocrine tumours,predictors,response to treatment, mTOR inhibitors, neuroendocrine tumours, predictors, response to treatment, Animal, medicine.disease, 030104 developmental biology, Immunology, Biomarkers, Resource utilization
Abstract

Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

Published
2015

32. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

33. Joint recommendations for the diagnosis and treatment of vulvo-vaginal atrophy in women in the peri- and post-menopausal phases from the Società Italiana per la Menopausa (SIM) and the Società Italiana della Terza Età (SIGiTE)

Author

Cagnacci, A., Gallo, M., Gambacciani, M., Lello, S., Volpe, A, Lanzone, A, Di Carlo, C, De Leo, V, Biglia, N, Caruso, S, Cicinelli, E, Farris, M, Gambera, A, Guaschino, S, Paoletti, Am, Russo, N, Vicariotto, F, Villa, P, Nocera, F, Maffei, S, Pandolfo, M, Ambroggio, S, Grassi, G, De Seta, F, Stomati, M, Gullo, D, Becorpi, A, Cancellieri, F, Fiorillo, F, Del Pup, L, Mapell, C, and Ottanelli, S.

Subjects
medicine.medical_specialty, Peri, Vaginal Diseases, Post menopausal, Guideline, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, Quality of life, Laser therapy, Diagnosis, medicine, Humans, Physician-Patient Relations, 030219 obstetrics & reproductive medicine, Postmenopausal women, Obstetrics, business.industry, Obstetrics and Gynecology, Atrophy, Postmenopause, medicine.disease, Perimenopause, Female, Quality of Life, Vulvar Diseases, 030220 oncology & carcinogenesis, Vaginal atrophy, business
Abstract

Herein, joint recommendations for diagnosis and treatment of vulvo-vaginal atrophy (VVA) in women in the peri- and post-menopausal phases from the Societa Italiana per la Menopausa (SIM) and the Societa Italiana della Terza Eta (SIGiTE) are presented. The recommendations are aimed at all healthcare personnel caring for women in the menopausal transition or postmenopausal phase, and are also intended to raise awareness of VVA. Recent data clearly indicate VVA is a highly prevalent condition among postmenopausal women, and that the vast majority of women with VVA are not adequately treated. In reality, diagnosis of VVA is simple and largely clinical. Many types of treatments are available for VVA, ranging from preventive education measures to local non-hormonal therapies, local agents that modulate hormonal receptors and systemic as well as laser therapy and radiofrequency. Regardless of the therapeutic approach adopted, greater communication between the physician and the woman with VVA should be actively encouraged. This is also in light of the difficulty of talking about the VVA and related disorders. Greater communication also encourages adequate therapy and thus minimizes the impact of VVA on the quality of life of the woman and her partner.

Published
2019

34. In-memory computing on a photonic platform

Author

Ríos, C, Youngblood, N, Cheng, Z, Gallo, M, Pernice, W, Wright, C, Sebastian, A, and Bhaskaran, H

Subjects
FOS: Computer and information sciences, Emerging Technologies (cs.ET), Computer Science - Emerging Technologies, FOS: Physical sciences, Physics - Applied Physics, Applied Physics (physics.app-ph), Physics - Optics, Optics (physics.optics)
Abstract

Collocated data processing and storage are the norm in biological systems. Indeed, the von Neumann computing architecture, that physically and temporally separates processing and memory, was born more of pragmatism based on available technology. As our ability to create better hardware improves, new computational paradigms are being explored. Integrated photonic circuits are regarded as an attractive solution for on-chip computing using only light, leveraging the increased speed and bandwidth potential of working in the optical domain, and importantly, removing the need for time and energy sapping electro-optical conversions. Here we show that we can combine the emerging area of integrated optics with collocated data storage and processing to enable all-photonic in-memory computations. By employing non-volatile photonic elements based on the phase-change material, Ge2Sb2Te5, we are able to achieve direct scalar multiplication on single devices. Featuring a novel single-shot Write/Erase and a drift-free process, such elements can multiply two scalar numbers by mapping their values to the energy of an input pulse and to the transmittance of the device, codified in the crystallographic state of the element. The output pulse, carrying the information of the light-matter interaction, is the result of the computation. Our all-optical approach is novel, easy to fabricate and operate, and sets the stage for development of entirely photonic computers.

Published
2019

35. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing (vol 51, pg 414, 2019)

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Damotte, V, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Moreno-Grau, S, Olaso, R, Raybould, R, Chen, YN, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, LM, Bacq, D, Denning, N, Jian, XQ, Zhao, Y, Del Zompo, M, Fox, NC, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Sanchez-Garcia, F, Patel, Y, Brody, JA, Dombroski, BA, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewicz, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, WS, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Sordon, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Munoz-Fernadez, C, Sussams, R, Lin, HH, Fairchild, TJ, Benito, YA, Holmes, C, Karamujic-Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roshchupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernandez, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth, WT, Montine, TJ, Frisardi, V, Diez-Fairen, M, Rivadeneira, F, Petersen, RC, Deramecourt, V, Alvarez, I, Salani, F, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AGA, Royall, DR, Dufouil, C, Maletta, RG, de Rojas, I, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Quintela, I, Carracedo, A, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frolich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JA, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JSK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, CH, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Kolsch, H, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hull, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, GE, Jin, LW, Leonenko, G, Real, LM, Jun, GR, Baldwin, CT, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jockel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nothen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, Mckee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O'Bryant, S, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, WR, Mead, S, Peskind, E, Cribbs, DH, Rossor, M, Pierce, A, Ryan, NS, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Caltagirone, C, Bossu, P, Orfei, MD, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Slifer, S, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tang, M, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Saba, Y, Pilotto, A, Bullido, MJ, Peters, O, Crane, PK, Bennett, D, Bosco, P, Coto, E, Boccardi, V, De Jager, PL, Lleo, A, Warner, N, Lopez, OL, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Nicolas, G, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Clarimon, J, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O'Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ramirez, A, Wang, LS, Ruiz, A, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, ADGC, EADI, Cohorts Heart Aging Res Genomic, and Genetic Environm Risk AD Defining

Published
2019

36. All-photonic in-memory computing based on phase-change materials

Author

Rios, C, Youngblood, N, Cheng, Z, Le Gallo, M, Pernice, WHP, Wright, CD, Sebastian, A, and Bhaskaran, H

Abstract

We experimentally demonstrate, for the first time, co-located data storage and processing (i.e. in-memory computing) on an integrated photonic platform based on nonvolatile phase-change materials.

Published
2019

38. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing

Author

KUNKLE, B. W., GRENIER-BOLEY, B., SIMS, R., BIS, J. C., DAMOTTE, V., NAJ, A. C., BOLAND, A., VRONSKAYA, M., VAN DER LEE, S. J., AMLIE-WOLF, A., BELLENGUEZ, C., FRIZATTI, A., CHOURAKI, V., MARTIN, E. R., SLEEGERS, K., BADARINARAYAN, N., JAKOBSDOTTIR, J., HAMILTON-NELSON, K. L., MORENO-GRAU, S., OLASO, R., RAYBOULD, R., CHEN, Y., KUZMA, A. B., HILTUNEN, M., MORGAN, T., AHMAD, S., VARDARAJAN, B. N., EPELBAUM, J., HOFFMANN, P., BOADA, M., BEECHAM, G. W., GARNIER, J. G., HAROLD, D., FITZPATRICK, A. L., VALLADARES, O., MOUTET, M. L., GERRISH, A., SMITH, A. V., QU, L., BACQ, D., DENNING, N., JIAN, X., ZHAO, Y., DEL ZOMPO, M., FOX, N. C., CHOI, S. H., MATEO, I., HUGHES, J. T., ADAMS, H. H., MALAMON, J., SANCHEZ-GARCIA, F., PATEL, Y., BRODY, J. A., DOMBROSKI, B. A., NARANJO, M. C. D., DANIILIDOU, M., EIRIKSDOTTIR, G., MUKHERJEE, S., WALLON, D., UPHILL, J., ASPELUND, T., CANTWELL, L. B., GARZIA, F., GALIMBERTI, D., HOFER, E., BUTKIEWICZ, M., FIN, B., SCARPINI, E., SARNOWSKI, C., BUSH, W. S., MESLAGE, S., KORNHUBER, J., WHITE, C. C., SONG, Y., BARBER, R. C., ENGELBORGHS, S., SORDON, S., VOIJNOVIC, D., ADAMS, P. M., VANDENBERGHE, R., MAYHAUS, M., CUPPLES, L. A., ALBERT, M. S., DE DEYN, P. P., GU, W., HIMALI, J. J., BEEKLY, D., SQUASSINA, A., HARTMANN, A. M., ORELLANA, A., BLACKER, D., RODRIGUEZ-RODRIGUEZ, E., LOVESTONE, S., GARCIA, M. E., DOODY, R. S., MUNOZ-FERNADEZ, C., SUSSAMS, R., LIN, H., FAIRCHILD, T. J., BENITO, Y. A., HOLMES, C., KARAMUJIC-COMIC, H., FROSCH, M. P., THONBERG, H., MAIER, W., ROSCHUPKIN, G., GHETTI, B., GIEDRAITIS, V., KAWALIA, A., LI, S., HUEBINGER, R. M., KILANDER, L., MOEBUS, S., HERNANDEZ, I., KAMBOH, M. I., BRUNDIN, R., TURTON, J., YANG, Q., KATZ, M. J., CONCARI, L., LORD, J., BEISER, A. S., KEENE, C. D., HELISALMI, S., KLOSZEWSKA, I., KUKULL, W. A., KOIVISTO, A. M., LYNCH, A., TARRAGA, L., LARSON, E. B., HAAPASALO, A., LAWLOR, B., MOSLEY, T. H., LIPTON, R. B., SOLFRIZZI, V., GILL, M., LONGSTRETH, W. T. Jr., MONTINE, T. J., FRISARDI, V., DIEZ-FAIREN, M., RIVADENEIRA, F., PETERSEN, R. C., DERAMECOURT, V., ALVAREZ, I., SALANI, F., CIARAMELLA, A., BOERWINKLE, E., REIMAN, E. M., FIEVET, N., ROTTER, J. I., REISCH, J. S., HANON, O., CUPIDI, C., ANDRE UITTERLINDEN, A. G., ROYALL, D. R., DUFOUIL, Carole, MALETTA, R. G., DE ROJAS, I., SANO, M., BRICE, A., CECCHETTI, R., GEORGE-HYSLOP, P. S., RITCHIE, K., TSOLAKI, M., TSUANG, D. W., DUBOIS, B., CRAIG, D., WU, C. K., SOININEN, H., AVRAMIDOU, D., ALBIN, R. L., FRATIGLIONI, L., GERMANOU, A., APOSTOLOVA, L. G., KELLER, L., KOUTROUMANI, M., ARNOLD, S. E., PANZA, F., GKATZIMA, O., ASTHANA, S., HANNEQUIN, D., WHITEHEAD, P., ATWOOD, C. S., CAFFARRA, P., HAMPEL, H., QUINTELA, I., CARRACEDO, A., LANNFELT, L., RUBINSZTEIN, D. C., BARNES, L. L., PASQUIER, F., FROLICH, L., BARRAL, S., MCGUINNESS, B., BEACH, T. G., JOHNSTON, J. A., BECKER, J. T., PASSMORE, P., BIGIO, E. H., SCHOTT, J. M., BIRD, T. D., WARREN, J. D., BOEVE, B. F., LUPTON, M. K., BOWEN, J. D., PROITSI, P., BOXER, A., POWELL, J. F., BURKE, J. R., KAUWE, J. S. K., BURNS, J. M., MANCUSO, M., BUXBAUM, J. D., BONUCCELLI, U., CAIRNS, N. J., MCQUILLIN, A., CAO, C., LIVINGSTON, G., CARLSON, C. S., BASS, N. J., CARLSSON, C. M., HARDY, J., CARNEY, R. M., BRAS, J., CARRASQUILLO, M. M., GUERREIRO, R., ALLEN, M., CHUI, H. C., FISHER, E., MASULLO, C., CROCCO, E. A., DECARLI, C., BISCEGLIO, G., DICK, M., MA, L., DUARA, R., GRAFF-RADFORD, N. R., EVANS, D. A., HODGES, A., FABER, K. M., SCHERER, M., FALLON, K. B., RIEMENSCHNEIDER, M., FARDO, D. W., HEUN, R., FARLOW, M. R., KOLSCH, H., FERRIS, S., LEBER, M., FOROUD, T. M., HEUSER, I., GALASKO, D. R., GIEGLING, I., GEARING, M., HULL, M., GESCHWIND, D. H., GILBERT, J. R., MORRIS, J., GREEN, R. C., MAYO, K., GROWDON, J. H., FEULNER, T., HAMILTON, R. L., HARRELL, L. E., DRICHEL, D., HONIG, L. S., CUSHION, T. D., HUENTELMAN, M. J., HOLLINGWORTH, P., HULETTE, C. M., HYMAN, B. T., MARSHALL, R., JARVIK, G. P., MEGGY, A., ABNER, E., MENZIES, G. E., JIN, L. W., LEONENKO, G., REAL, L. M., JUN, G. R., BALDWIN, C. T., GROZEVA, D., KARYDAS, A., RUSSO, G., KAYE, J. A., KIM, R., JESSEN, F., KOWALL, N. W., VELLAS, B., KRAMER, J. H., VARDY, E., LAFERLA, F. M., JOCKEL, K. H., LAH, J. J., DICHGANS, M., LEVERENZ, J. B., MANN, D., LEVEY, A. I., PICKERING-BROWN, S., LIEBERMAN, A. P., KLOPP, N., LUNETTA, K. L., WICHMANN, H. E., LYKETSOS, C. G., MORGAN, K., MARSON, D. C., BROWN, K., MARTINIUK, F., MEDWAY, C., MASH, D. C., NOTHEN, M. M., MASLIAH, E., HOOPER, N. M., MCCORMICK, W. C., DANIELE, A., MCCURRY, S. M., BAYER, A., MCDAVID, A. N., GALLACHER, J., MCKEE, A. C., VAN DEN BUSSCHE, H., MESULAM, M., BRAYNE, C., MILLER, B. L., RIEDEL-HELLER, S., MILLER, C. A., MILLER, J. W., AL-CHALABI, A., MORRIS, J. C., SHAW, C. E., MYERS, A. J., WILTFANG, J., O'BRYANT, S., OLICHNEY, J. M., ALVAREZ, V., PARISI, J. E., SINGLETON, A. B., PAULSON, H. L., COLLINGE, J., PERRY, W. R., MEAD, S., PESKIND, E., CRIBBS, D. H., ROSSOR, M., PIERCE, A., RYAN, N. S., POON, W. W., NACMIAS, B., POTTER, H., SORBI, S., QUINN, J. F., SACCHINELLI, E., RAJ, A., SPALLETTA, G., RASKIND, M., CALTAGIRONE, C., BOSSU, P., ORFEI, M. D., REISBERG, B., CLARKE, R., REITZ, C., SMITH, A. D., RINGMAN, J. M., WARDEN, D., ROBERSON, E. D., WILCOCK, G., ROGAEVA, E., BRUNI, A. C., ROSEN, H. J., GALLO, M., ROSENBERG, R. N., BEN-SHLOMO, Y., SAGER, M. A., MECOCCI, P., SAYKIN, A. J., PASTOR, P., CUCCARO, M. L., VANCE, J. M., SCHNEIDER, J. A., SCHNEIDER, L. S., SLIFER, S., SEELEY, W. W., SMITH, A. G., SONNEN, J. A., SPINA, S., STERN, R. A., SWERDLOW, R. H., TANG, M., TANZI, R. E., TROJANOWSKI, J. Q., TRONCOSO, J. C., VAN DEERLIN, V. M., VAN ELDIK, L. J., VINTERS, H. V., VONSATTEL, J. P., WEINTRAUB, S., WELSH-BOHMER, K. A., WILHELMSEN, K. C., WILLIAMSON, J., WINGO, T. S., WOLTJER, R. L., WRIGHT, C. B., YU, C. E., YU, L., SABA, Y., ALZHEIMER DISEASE GENETICS, Consortium, EUROPEAN ALZHEIMER'S DISEASE, Initiative, COHORTS FOR, Heart, AGING RESEARCH IN GENOMIC EPIDEMIOLOGY, Consortium, GENETIC ENVIRONMENTAL RISK IN AD/DEFINING GENETIC, Polygenic, ENVIRONMENTAL RISK FOR ALZHEIMER'S DISEASE, Consortium, PILOTTO, A., BULLIDO, M. J., PETERS, O., CRANE, P. K., BENNETT, D., BOSCO, P., COTO, E., BOCCARDI, V., DE JAGER, P. L., LLEO, A., WARNER, N., LOPEZ, O. L., INGELSSON, M., DELOUKAS, P., CRUCHAGA, C., GRAFF, C., GWILLIAM, R., FORNAGE, M., GOATE, A. M., SANCHEZ-JUAN, P., KEHOE, P. G., AMIN, N., ERTEKIN-TANER, N., BERR, C., DEBETTE, Stephanie, LOVE, S., LAUNER, L. J., YOUNKIN, S. G., DARTIGUES, Jean-Francois, CORCORAN, C., IKRAM, M. A., DICKSON, D. W., NICOLAS, G., CAMPION, D., TSCHANZ, J., SCHMIDT, H., HAKONARSON, H., CLARIMON, J., MUNGER, R., SCHMIDT, R., FARRER, L. A., VAN BROECKHOVEN, C., M, C. O' Donovan, DESTEFANO, A. L., JONES, L., HAINES, J. L., DELEUZE, J. F., OWEN, M. J., GUDNASON, V., MAYEUX, R., ESCOTT-PRICE, V., PSATY, B. M., RAMIREZ, A., WANG, L. S., RUIZ, A., VAN DUIJN, C. M., HOLMANS, P. A., SESHADRI, S., WILLIAMS, J., AMOUYEL, P., SCHELLENBERG, G. D., LAMBERT, J. C., PERICAK-VANCE, M. A., Epidemiology, Internal Medicine, Neurology, Radiology & Nuclear Medicine, Amsterdam Reproduction & Development (AR&D), Clinical sciences, Pathologic Biochemistry and Physiology, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Medizin, Gene Expression, genetics [Alzheimer Disease], Genome-wide association study, methods [Genome-Wide Association Study], SEPIA, Genome-wide association studies, genetic meta-analysis, 0302 clinical medicine, genetics [Immunity], genetics [Amyloid beta-Peptides], genetics, tau, genetics [Genetic Predisposition to Disease], new risk loci, Aβ, Genetics, Medicine(all), 0303 health sciences, medicine.diagnostic_test, Alzheimer's disease, Lipids, 3. Good health, Settore MED/26 - NEUROLOGIA, VINTAGE, Female, Amyloid beta, methods [Genetic Testing], Tau protein, lipid processing, tau Proteins, genetics [Genetic Loci], Biology, Article, FR, 03 medical and health sciences, Alzheimer Disease, ddc:570, genetics [Haplotypes], medicine, Genetic predisposition, Humans, Dementia, Genetic Predisposition to Disease, Genetic Testing, LOAD, genetics [Lipids], Risk factor, immunity, Aged, 030304 developmental biology, Genetic testing, Amyloid beta-Peptides, Lipid Metabolism, medicine.disease, Gene expression, genetics [tau Proteins], Haplotypes, Genetic Loci, Case-Control Studies, genetics [Lipid Metabolism], genome-wide association studies, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, dementia
Abstract

Risk for late-onset Alzheimers disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimers or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimers disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 ׫2009»10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

39. The role of the intensive care unit in real-time surveillance of emerging pandemics: the Italian GiViTI experience

Author

Bertolini, G, Nattino, G, Langer, M, Tavola, M, Crespi, D, Mondini, M, Rossi, C, Previtali, C, Marshall, J, Poole, D, Abascià, A, Acquarolo, A, Adorni, A, Agnelli, V, Agostini, F, Alampi, D, Alberti, A, Alborghetti, A, Alleva, S, Ambrosoni, S, Antonini, B, Arditi, E, Avalli, L, Babini, M, Bagalini, G, Balata, A, Balicco, B, Barbagallo, M, Bartoli, T, Bassi, G, Becarelli, S, Beck, E, Bellin, M, Bellonzi, A, Bellorini, M, Benanti, C, Bensi, M, Bernasconi, Mo, Berruto, F, Bertolini, R, Besozzi, A, Biamino, C, Bianchi, T, Bianchin, A, Boccalatte, D, Bocchi, A, Bonaccorso, G, Bonazzi, M, Balsamo, C, Bonicalzi, V, Boniotti, C, Bonizzoli, M, Bottazzi, A, Breschi, C, Brizio, E, Brunetti, B, Brunori, E, Bubbico, G, Buscaglia, G, Calicchio, G, Calligaro, P, Calva, S, Candido, M, Capitanio, G, Caroleo, S, Casagli, S, Casalini, P, Castiglione, G, Cerana, M, Chiani, C, Chierego, G, Ciani, A, Ciceri, R, Cigada, Mg, Cima, M, Cingolani, E, Cinque, E, Coletta, Rp, Colombo, L, Colombo, R, Converso, M, Corrado, A, Cortis, G, Costagli, V, Crema, L, Crestan, E, Da, D, Cero, Pd, Ferro, Md, De Blasi RA, De Blasio, E, De Cristofaro MG, De Luca, A, Di Pasquale, D, Doroni, L, Fabi, Mc, Facondini, F, Fagoni, Nazzareno, Falzetti, G, Faraldi, L, Fiore, G, Fiume, C, Galeotti, E, Galleschi, N, Gallo, M, Gamberini, E, Garelli, A, Giacomello, S, Gianni, M, Giudici, R, Giuntini, R, Gnesin, P, Gorietti, A, Grassitelli, S, Greco, M, Irpino, A, Guadagna, A, Guadagnucci, A, Guagliardi, C, Laici, C, Lain, G, Lanza, G, Lefons, U, Leggieri, C, Lembo, R, Librenti, M, Liverani, C, Longobardo, A, Madeira, Sm, Madonna, R, Magatti, Mf, Mamprin, F, Mannolini, G, Marafon, S, Marchesi, G, Marifoglou, D, Martinelli, P, Martinelli, S, Escobar, Rm, Mastroianni, A, Mastropierro, R, Mediani, Ts, Messina, M, Milan, B, Molesi, A, Alberto, Cm, Mongelli, P, Morigi, A, Mosti, G, Muttini, S, Nardini, M, Nascimben, E, Natalini, G, Negri, G, Negro, G, Neri, M, Netto, R, Nonini, S, Odetto, L, Olivieri, C, Candida, Mo, Osti, D, Palmer, M, Parnigotto, A, Parrini, V, Pasculli, M, Pasetti, G, Passafiume, M, Pastorini, S, Patrignani, L, Pedeferri, M, Pegoraro, M, Pelati, E, Pelosi, G, Pera, L, Perino, P, Pero, A, Perzolla, D, Peta, M, Pinna, C, Pizzali, M, Postiglione, M, Potalivo, A, Raffaeli, M, Randellini, R, Rech, A, Renda, B, Ricciardi, G, Rizzi, S, Romagnoli, S, Rossi, G, Rossi, M, Rutta, C, Sagliaschi, U, Salcuni, R, Salvi, G, Scalera, M, Scarrone, S, Schiavuzzi, M, Aurelio, Ps, Selvaggi, P, Sicignano, A, Sorbara, C, Spagarino, E, Sparicio, D, Spinazzola, Ar, Sucre, Mj, Terzitta, M, Tetamo, R, Tibaldi, G, Todesco, L, Tomaselli, P, Torta, M, Turriziani, I, Ughi, L, Vaccari, C, Vaj, M, Vanzino, R, Vardanega, A, Vecchiarelli, P, Vedovati, S, Zanni, V, Zappa, S, Zardin, M, Zaro, G, Zuccaro, F, Barattini, M, Chieregato, A, Fumagalli, R, Livigni, S, Mengoli, F, Nardi, G, Palma, D, Portolani, L, Radrizzani, D, Terzitta, M., Bertolini, G, Nattino, G, Langer, M, Tavola, M, Crespi, D, Mondini, M, Rossi, C, Previtali, C, Marshall, J, Poole, D, Abascia, A, Acquarolo, A, Adorni, A, Agnelli, V, Agostini, F, Alampi, D, Alberti, A, Alborghetti, A, Alleva, S, Ambrosoni, S, Antonini, B, Arditi, E, Avalli, L, Babini, M, Bagalini, G, Balata, A, Balicco, B, Barbagallo, M, Bartoli, T, Bassi, G, Becarelli, S, Beck, E, Bellin, M, Bellonzi, A, Bellorini, M, Benanti, C, Bensi, M, Bernasconi, M, Berruto, F, Besozzi, A, Biamino, C, Bianchi, T, Bianchin, A, Boccalatte, D, Bocchi, A, Bonaccorso, G, Bonazzi, M, Balsamo, C, Bonicalzi, V, Boniotti, C, Bonizzoli, M, Bottazzi, A, Breschi, C, Brizio, E, Brunetti, B, Brunori, E, Bubbico, G, Buscaglia, G, Calicchio, G, Calligaro, P, Calva, S, Candido, M, Capitanio, G, Caroleo, S, Casagli, S, Casalini, P, Castiglione, G, Cerana, M, Chiani, C, Chierego, G, Ciani, A, Ciceri, R, Cigada, M, Cima, M, Cingolani, E, Cinque, E, Coletta, R, Colombo, L, Colombo, R, Converso, M, Corrado, A, Cortis, G, Costagli, V, Crema, L, Crestan, E, Da, D, Cero, P, Ferro, M, De Blasi, R, De Blasio, E, De Cristofaro, M, De Luca, A, Di Pasquale, D, Doroni, L, Fabi, M, Facondini, F, Fagoni, N, Falzetti, G, Faraldi, L, Fiore, G, Fiume, C, Galeotti, E, Galleschi, N, Gallo, M, Gamberini, E, Garelli, A, Giacomello, S, Gianni, M, Giudici, R, Giuntini, R, Gnesin, P, Gorietti, A, Grassitelli, S, Greco, M, Irpino, A, Guadagna, A, Guadagnucci, A, Guagliardi, C, Laici, C, Lain, G, Lanza, G, Lefons, U, Leggieri, C, Lembo, R, Librenti, M, Liverani, C, Longobardo, A, Madeira, S, Madonna, R, Magatti, M, Mamprin, F, Mannolini, G, Marafon, S, Marchesi, G, Marifoglou, D, Martinelli, P, Martinelli, S, Escobar, R, Mastroianni, A, Mastropierro, R, Mediani, T, Messina, M, Milan, B, Molesi, A, Alberto, C, Mongelli, P, Morigi, A, Mosti, G, Muttini, S, Nardini, M, Nascimben, E, Natalini, G, Negri, G, Negro, G, Neri, M, Netto, R, Nonini, S, Odetto, L, Olivieri, C, Candida, M, Osti, D, Palmer, M, Parnigotto, A, Parrini, V, Pasculli, M, Pasetti, G, Passafiume, M, Pastorini, S, Patrignani, L, Pedeferri, M, Pegoraro, M, Pelati, E, Pelosi, G, Pera, L, Perino, P, Pero, A, Perzolla, D, Peta, M, Pinna, C, Pizzali, M, Postiglione, M, Potalivo, A, Raffaeli, M, Randellini, R, Rech, A, Renda, B, Ricciardi, G, Rizzi, S, Romagnoli, S, Rossi, G, Rossi, M, Rutta, C, Sagliaschi, U, Salcuni, R, Salvi, G, Scalera, M, Scarrone, S, Schiavuzzi, M, Aurelio, P, Selvaggi, P, Sicignano, A, Sorbara, C, Spagarino, E, Sparicio, D, Spinazzola, A, Sucre, M, Terzitta, M, Tetamo, R, Tibaldi, G, Todesco, L, Tomaselli, P, Torta, M, Turriziani, I, Ughi, L, Vaccari, C, Vaj, M, Vanzino, R, Vardanega, A, Vecchiarelli, P, Vedovati, S, Zanni, V, Zappa, S, Zardin, M, Zaro, G, Zuccaro, F, Barattini, M, Chieregato, A, Fumagalli, R, Livigni, S, Mengoli, F, Nardi, G, Palma, D, Portolani, L, and Radrizzani, D

Subjects
medicine.medical_specialty, Epidemiology, surveillance system, law.invention, 03 medical and health sciences, Influenza A Virus, H1N1 Subtype, 0302 clinical medicine, Public health surveillance, law, Infectious disease epidemiology, influenza, pandemic, Humans, Influenza, Human, Intensive Care Units, Italy, Public Health Surveillance, Pandemics, Pandemic, medicine, human, 030212 general & internal medicine, medicine (all), Intensive care medicine, business.industry, Public health, Outbreak, 030208 emergency & critical care medicine, Monitoring system, medicine.disease, Intensive care unit, infectious disease epidemiology, humans, influenza a virus, h1n1 subtype, intensive care units, italy, public health surveillance, pandemics, infectious diseases, epidemiology, Infectious Diseases, Human mortality from H5N1, Medical emergency, business
Abstract

SUMMARYThe prompt availability of reliable epidemiological information on emerging pandemics is crucial for public health policy-makers. Early in 2013, a possible new H1N1 epidemic notified by an intensive care unit (ICU) to GiViTI, the Italian ICU network, prompted the re-activation of the real-time monitoring system developed during the 2009–2010 pandemic. Based on data from 216 ICUs, we were able to detect and monitor an outbreak of severe H1N1 infection, and to compare the situation with previous years. The timely and correct assessment of the severity of an epidemic can be obtained by investigating ICU admissions, especially when historical comparisons can be made.

Published
2015

40. CXCR4involvement in neurodegenerative diseases

Author

Bonham, Luke W, Karch, Celeste M, Ferrari, Raffaele, Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Hardy, John, Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Momeni, Parastoo, Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Höglinger, Günter, Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Müller, Ulrich, Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Hess, Christopher P, Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., van Swieten, J. C., Dopper, E. G. P., Sugrue, Leo P, Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Dillon, William P, Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Schellenberg, Gerard D, Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Miller, Bruce L, Fan, Chun C, Andreassen, Ole A, Dale, Anders M, Barkovich, A James, Yokoyama, Jennifer S, Desikan, Rahul S, Consortium, International FTD-Genomics, Consortium, International Parkinson’s Disease Genetics, Project, International Genomics of Alzheimer’s, Ferrari, R., Hernandez, D. G., Tan, Chin, Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Geier, Ethan G, Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Wang, Yunpeng, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Wen, Natalie, Blesa, R., Waldö, M Landqvist, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Broce, Iris J, Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Li, Yi, Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Barkovich, Matthew J, Rogaeva, E., George-Hyslop, P St, Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Bonham, Luke W., Karch, Celeste M., Fan, Chun C., Tan, Chin, Geier, Ethan G., Wang, Yunpeng, Wen, Natalie, Broce, Iris J., Li, Yi, Barkovich, Matthew J., Ferrari, Raffaele, Hardy, John, Momeni, Parastoo, Höglinger, Günter, Müller, Ulrich, Hess, Christopher P., Sugrue, Leo P., Dillon, William P., Schellenberg, Gerard D., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Barkovich, A. Jame, Yokoyama, Jennifer S., Desikan, Rahul S., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Waldö, M. Landqvist., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., George-Hyslop, P. St., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Van Der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Karydas, A. M., Rosen, H., Van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Rademakers, Rosa, International FTD-Genomics Consortium (IFGC), International Parkinsons Disease Genetics Consortium (IPDGC), and International Genomics of Alzheimers Project (IGAP)

Subjects
0301 basic medicine, Aging, Gene Expression, Genome-wide association study, metabolism [Microglia], Neurodegenerative, Bioinformatics, Alzheimer's Disease, Transgenic, Mice, 0302 clinical medicine, Risk Factors, Receptors, 2.1 Biological and endogenous factors, Psychology, Gene Regulatory Networks, Aetiology, Alzheimer's Disease Related Dementias (ADRD), 0303 health sciences, Gene Regulatory Network, Parkinson's Disease, International Genomics of Alzheimer’s Project, Neurodegeneration, Brain, Neurodegenerative Diseases, Single Nucleotide, International Parkinson’s Disease Genetics Consortium, Frontotemporal Dementia (FTD), Psychiatry and Mental Health, Neurological, Public Health and Health Services, Tauopathy, Microglia, Frontotemporal dementia, Human, Receptors, CXCR4, Tau protein, Clinical Sciences, Mice, Transgenic, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, CXCR4 protein, human, Progressive supranuclear palsy, lcsh:RC321-571, Cellular and Molecular Neuroscience, 03 medical and health sciences, Rare Diseases, Text mining, Genetic predisposition, medicine, Genetics, Acquired Cognitive Impairment, Animals, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, CXCR4, Neurodegenerative Disease, Animal, business.industry, Risk Factor, International FTD-Genomics Consortium, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, genetics [Receptors, CXCR4], Brain Disorders, Genome-Wide Association Study, 030104 developmental biology, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, biology.protein, Dementia, Human medicine, metabolism [Receptors, CXCR4], business, 030217 neurology & neurosurgery
Abstract

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Published
2017

41. Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management

Author

Altieri B., Di Dato C., Martini C., Sciammarella C., DI SARNO, ALFONSO, Colao A., Faggiano A., Albertelli M., AMBROSETTI, ENRICO MARIO, Bianchi A., Bottiglieri F., Campione S., Carra S., De Cicco F., Di Molfetta S., Fanciulli G., Ferone D., Ferrau F., Gallo M., Giannetta E., Grillo F., Maria E. G., Guadagno E., Guarnotta V., Isidori A., Lo Calzo F., Malandrino P., Messina E., Modica R., Muscogiuri G., Pizza G., Razzore P., Rizza L., Rubino M., Ruggeri R. M., Vitale G., Zatelli M. C., Altieri, B., Di Dato, C., Martini, C., Sciammarella, C., DI SARNO, Alfonso, Colao, A., Faggiano, A., Albertelli, M., Ambrosetti, ENRICO MARIO, Bianchi, A., Bottiglieri, F., Campione, S., Carra, S., De Cicco, F., Di Molfetta, S., Fanciulli, G., Ferone, D., Ferrau, F., Gallo, M., Giannetta, E., Grillo, F., Maria, E. G., Guadagno, E., Guarnotta, V., Isidori, A., Lo Calzo, F., Malandrino, P., Messina, E., Modica, R., Muscogiuri, G., Pizza, G., Razzore, P., Rizza, L., Rubino, M., Ruggeri, R. M., Vitale, G., and Zatelli, M. C.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Prognosi, Skeletal-related event, education, Skeletal related events, 030209 endocrinology & metabolism, Review, lcsh:RC254-282, Pathogenesis, Bone metastases, Bone microenvironment, Denosumab, Epithelial-to-mesenchymal transition, Microrna, Neuroendocrine neoplasms, Prognosis, Skeletal-related events, Treatment, 03 medical and health sciences, 0302 clinical medicine, bone metastases, Quality of life, Internal medicine, medicine, neuroendocrine neoplasms, microRNA, treatment, medicine.diagnostic_test, business.industry, digestive, oral, and skin physiology, denosumab, Retrospective cohort study, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, skeletal-related events, Neuroendocrine neoplasm, Clinical Practice, Bone metastase, stomatognathic diseases, Positron emission tomography, Curative treatment, 030220 oncology & carcinogenesis, epithelial-to-mesenchymal transition, prognosis, business, bone microenvironment, medicine.drug
Abstract

Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient’s quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice.

Published
2019

42. Biomimicry: 'Leren van de natuur voor duurzame oplossingen'

Author

Gallo, M.

Subjects
Biomimicry
Abstract

Biomimicry wordt vooral verbonden aan technologische ontwikkelingen. Er zijn veel voorbeelden van producten en innovaties op basis van de biologie. Ingenieurs, architecten, ontwerpers maken gebruik van nieuwe kennis die we hebben opgedaan en opdoen door met moderne middelen de natuur te bestuderen. Mauro Gallo geeft hiervan voorbeelden en gaat daar verder onderzoek naar doen. Van de natuur in haar geheel is meer te leren. In de praktijk van onderwijs, training,advies, consultancy en organisatieontwikkeling, wordt ‘de natuur’ vaak gebruikt als metafoor, als inspiratiebron of als voorbeeld voor allerlei processen zoals leiderschap, samenwerkingen, relaties, en de ontwikkeling van organisaties en de samenleving. Het gaat daarbij veelal over ecologische en veel minder vaak over biologische processen. Langzaam heeft zich de vraag opgedrongen of we in de sociale omgeving meer kunnen leren uit de natuur dan wat we oppervlakkig ‘zien’ en vaak in metaforen vertaald wordt. Meer holistisch bezien gaat het hier over de systemische kant, de complexiteit, de context en de samenhang. Kunnen we bijvoorbeeld aantonen dat fundamentele ecologische principes zoals kringlopen (lerend, zelf organiserend, zelfregulerend en zelfvoorzienend vermogen), successie, diversiteit en veerkracht, sociaal en samenwerkend gedrag, interconnectedness en interdependency toepassen in organisaties leiden tot duurzaam organiseren? In zijn lectoraat doet Mauro Gallo onderzoek naar de betekenis van technische innovaties in en voor de agro- en food sector, en naar de vraag of biomimicry onderbouwd kan worden zodat het bij kan dragen aan het sociaal wetenschappelijk domein. Tegelijkertijd is er een gerichte onderwijsvraag: is het logisch om vanuit ons groene DNA biomimicry-denken mee te nemen in ons onderwijs? Kun je biomimicry leren toepassen en kun je biomimicry toepassen in leren? (Hoe) kunnen we biomimicry toepassen in vmbo en mbo groen, in de lerarenopleiding meegeven aan toekomstige leraren, en opnemen in de professionalisering voor zittende docenten. Is het denkbaar dat het integraal onderdeel van de curricula in het (groene) hbo wordt gericht op het zoeken naar duurzame oplossingen voor vraagstukken in de beroepspraktijk? Zoals hierboven geschetst: genoeg praktijkvragen voor een lectoraat. Daarbij richt het zich echter niet alleen op het toepassen, maar nadrukkelijk op het wetenschappelijk onderbouwen van bio-inspired oplossingen en op het onderwijs.

Published
2018

43. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Aloso, R, Raybould, R, Chen, Y, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Zompo, MD, Fox, NC, Grove, ML, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Garcia, FS, Patel, Y, Brody, JA, Dombroski, B, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewics, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Pichler, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Fernadez, CM, Sussams, R, Lin, H, Fairchild, TJ, Benito, YA, Holmes, C, Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernández, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth Jr, WT, Montine, TJ, Frisardi, V, Ortega-Cubero, S, Rivadeneira, F, Petersen, RC, Deramecourt, V, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Caltagirone, C, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AG, Royall, DR, Dufouil, C, Maletta, RG, Moreno-Grau, S, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Baldwin, CT, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JI, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, C, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Cribbs, DH, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hüll, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, G, Jin, LW, Leonenko, G, Jun, G, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jöckel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nöthen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, McKee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O’Bryant, S, Coto, E, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, W, Mead, S, Peskind, E, Rosser, M, Pierce, A, Ryan, N, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Bossù, P, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Crane, PK, Bennett, DA, Boccardi, V, De Jager, PL, Warner, N, Lopez, OL, McDonough, S, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O’Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ruiz, A, Ramirez, A, Wang, LS, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, Bis, JC [0000-0002-3409-1110], Garnier, JG [0000-0003-4991-763X], Smith, AV [0000-0001-9088-234X], Denning, N [0000-0001-8467-7382], Vandenberghe, R [0000-0001-6237-2502], Himali, JJ [0000-0003-1391-9481], Rodriguez-Rodriguez, E [0000-0001-7742-677X], Frisardi, V [0000-0003-0764-7387], Ortega-Cubero, S [0000-0003-0520-9439], Hanon, O [0000-0002-4697-122X], Brice, A [0000-0002-0941-3990], Albin, RL [0000-0002-0629-608X], Buxbaum, JD [0000-0001-8898-8313], Bass, NJ [0000-0002-4481-778X], Fisher, E [0000-0003-2850-9936], Bayer, A [0000-0002-7514-248X], Gallacher, J [0000-0002-2394-5299], Brayne, C [0000-0001-5307-663X], Riedel-Heller, S [0000-0003-4321-6090], Al-Chalabi, A [0000-0002-4924-7712], and Apollo - University of Cambridge Repository

Subjects
Aging, 4202 Epidemiology, Genome-wide association study, Disease, Neurodegenerative, Biology, 3101 Biochemistry and Cell Biology, Alzheimer's Disease, 3105 Genetics, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Acquired Cognitive Impairment, Genetics, medicine, 2.1 Biological and endogenous factors, Dementia, Gene, 030304 developmental biology, Genetic association, 2 Aetiology, 0303 health sciences, Prevention, Human Genome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Lipid metabolism, medicine.disease, Brain Disorders, 3. Good health, Meta-analysis, Neurological, Alzheimer's disease, 030217 neurology & neurosurgery, 31 Biological Sciences
Abstract

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

Published
2018
Full Text
View/download PDF

44. Perioperative and Periprocedural Management of Antithrombotic Therapy: Consensus Document of SEC, SEDAR, SEACV, SECTCV, AEC, SECPRE, SEPD, SEGO, SEHH, SETH, SEMERGEN, SEMFYC, SEMG, SEMICYUC, SEMI, SEMES, SEPAR, SENEC, SEO, SEPA, SERVE', SECOT and AEU

Author

Vivas, D, Roldan, I, Ferrandis, R, Marin, F, Roldan, V, Tello-Montoliu, A, Ruiz J, Jose Gomez-Doblas, J, Martin, A, Vicente Llau, J, Jose Ramos-Gallo, M, Munoz, R, Ignacio Arcelus, J, Leyva, F, Alberca, F, Oliva, R, Maria Gomez, A, Montero, C, Arikans, F, Ley, L, Santos-Buesou, E, Figuero, E, Bujaldon, A, Urbane, J, Otero, R, Francisco Hermida, J, Egocheaga, I, Luis Llisterri, J, Maria Lobos, J, Serrano, A, Madridano, O, Luis Ferreiro, J, Cassinello, C, Gomez-Luque, A, Hidalgo, F, Sierra, P, Marco P, Mateo Arranza, J, Palomo, V, Guerrero, A, Anguita, M, and Iniguez, A

Subjects
Anticoagulation, Antithrombotic, Antiplatelet, Surgery
Abstract

During the last few years, the number of patients receiving anticoagulant and antiplatelet therapy has increased worldwide. Since this is a chronic treatment, patients receiving it can be expected to need some kind of surgery or intervention during their lifetime that may require treatment discontinuation. The decision to withdraw antithrombotic therapy depends on the patient's thrombotic risk versus hemorrhagic risk. Assessment of both factors will show the precise management of anticoagulant and antiplatelet therapy in these scenarios. The aim of this consensus document, coordinated by the Cardiovascular Thrombosis Working Group of the Spanish Society of Cardiology, and endorsed by most of the Spanish scientific societies of clinical specialities that may play a role in the patient-health care process during the perioperative or periprocedural period, is to recommend some simple and practical guidelines with a view to homogenizing daily clinical practice. Full English text available from: www.revespcardiol.org/en (C) 2018 Sociedad Espafiola de Cardiologia. Published by Elsevier Espania, S.L.U. All rights reserved.

Published
2018

48. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsuing GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wasserman EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky E, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossmann M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutnik P, Snowden J, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Peterson RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P., Broce, Iris [0000-0003-4932-1430], Karch, Celeste M [0000-0002-6854-5547], Wang, Yunpeng [0000-0001-9831-1090], Tan, Chin Hong [0000-0002-0980-9936], Kouri, Naomi [0000-0002-6841-9882], Hess, Christopher P [0000-0002-5132-5302], Miller, Zachary A [0000-0002-5991-3053], Bonham, Luke W [0000-0002-2533-1266], Veldink, Jan H [0000-0001-5572-9657], Dale, Anders M [0000-0002-6126-2966], Desikan, Rahul S [0000-0002-4151-6017], Sugrue, Leo P [0000-0001-7315-4519], Apollo - University of Cambridge Repository, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Divisions, Rademakers, Rosa, Int FTD-Genomics Consortium, Broce, Iri, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsuing, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wasserman, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, E, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossmann, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutnik, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Peterson, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Linkage disequilibrium, Gene Expression, Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Motor Neuron Diseases, 0302 clinical medicine, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Corticobasal degeneration, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], Genetics, Medicine (all), Neurodegenerative Diseases, Single Nucleotide, Genomics, General Medicine, Middle Aged, Colitis, LRRK2, 3. Good health, Neurology, Manchester Institute for Collaborative Research on Ageing, Frontotemporal Dementia, Neurological, Medicine, Research Article, Frontotemporal dementia, ResearchInstitutes_Networks_Beacons/MICRA, Immunology, Rheumatoid Arthritis, Single-nucleotide polymorphism, Gastroenterology and Hepatology, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Rare Diseases, Rheumatology, Clinical Research, General & Internal Medicine, FTD GWA, Mental Health and Psychiatry, mental disorders, Acquired Cognitive Impairment, Genome-Wide Association Studies, medicine, Ulcerative Colitis, Humans, Inflammatory and Immune System, Genetic Predisposition to Disease, ddc:610, Polymorphism, Aged, Genetic association, Genome-Wide Association Study, International FTD-Genomics Consortium, Prevention, Arthritis, Human Genome, Inflammatory Bowel Disease, Amyotrophic Lateral Sclerosis, Neurosciences, Correction, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Human Genetics, Genome Analysis, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genetic Loci, Genetics of Disease, Dementia, Clinical Immunology, Human medicine, Clinical Medicine, Digestive Diseases, 030217 neurology & neurosurgery
Abstract

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD., Rahul Desikan and colleagues use summary data from genome-wide association studies to investigate genetic overlap between frontotemporal dementia and a several immune-mediated diseases, and identify microglia and inflammation-associated genes that may play a role in FTD pathogenesis., Author summary Why was this study done? Frontotemporal dementia (FTD) is the leading cause of dementia in individuals less than 65 years old. Currently, there is no approved treatment of FTD and no diagnostic tests for predicting disease onset or measuring progression. Increasing evidence suggests that inflammation and immune system dysfunction play an important role in the pathogenesis of FTD. What did the researchers do and find? We used summary data from genome-wide association studies to investigate genetic overlap, or “pleiotropy,” between FTD and a variety of immune-mediated diseases. Through this approach, we found extensive FTD–immune genetic overlap within the HLA region on Chromosome 6, an area rich in genes related to microglial function, as well as in 3 genes not previously identified as contributing to the pathophysiology of FTD. Pointing to the functional relevance of these genetic results, we found that these candidate FTD–immune genes are differentially expressed in postmortem brains from patients with FTD compared to controls, and in microglia/macrophages compared with other central nervous system cells. Using bioinformatics tools, we explored protein and genetic interactions among our candidate FTD–immune genes. These results suggest that rather than a few individual loci, large portions of the HLA region may be associated with increased FTD risk. What do these findings mean? Immune dysfunction may play a role in the pathophysiology of a subset of FTD cases. For a subset of patients in whom immune dysfunction in general—and microglial activation in particular—is central to disease pathophysiology, anti-inflammatory treatment is an important area for further investigation.

Published
2018

49. Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

Author

Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, Veldink, Jh, van Es MA4, Smit, Ab5, Posthuma, D1, 2, Hernandez DG, Pijnenburg Y., Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, Roberta, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, Ps, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, GUNNAR MARKUS, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, Lara, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Egp, Seelaar, H, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Antonio, Milan, Gian Luca, Sorrentino, Paolo Luigi, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P., Rademakers, Rosa, International FTD-Genomics Consortium, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Quality of Care, Midwifery Science, Divisions, Neurology, Amsterdam Reproduction & Development (AR&D), Mishra, A [0000-0002-8141-1543], van der Sluis, S [0000-0001-9958-7216], van Es, MA [0000-0002-7709-5883], Posthuma, D [0000-0001-7582-2365], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Candidate gene, Science, Genome-wide association study, Biology, Neurodegenerative, Article, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, SDG 3 - Good Health and Well-being, mental disorders, medicine, Journal Article, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, General, Alzheimer's Disease Related Dementias (ADRD), Genetic association, Multidisciplinary, Genetic heterogeneity, International FTD-Genomics Consortium, Neurodegeneration, Human Genome, Neurosciences, nutritional and metabolic diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, nervous system diseases, Brain Disorders, Frontotemporal Dementia (FTD), 030104 developmental biology, DNA methylation, Neurological, Medicine, Dementia, Human medicine, ALS, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Published
2017

50. Immune-related genetic enrichment in frontotemporal dementia

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I R A, Hsiung, G-Y R, Mann, D M A, Grafman, J, Morris, C M, Attems, J, Griffiths, T D, McKeith, I G, Thomas, A J, Pietrini, P, Huey, E D, Wassermann, E M, Baborie, A, Jaros, E, Tierney, M C, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, P St, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J B, Schlachetzki, J C M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V M, Grossman, M, Trojanowski, J Q, der Zee, J van, Cruts, M, Broeckhoven, C Van, Cappa, S F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J E, Hjermind, L E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M N, Fox, N C, Warren, J D, Spillantini, M G, Morris, H R, Rizzu, P, Heutink, P, Snowden, J S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M E, Smirne, N, Rademakers, R, Baker, M, Dickson, D W, Graff-Radford, N R, Petersen, R C, Knopman, D, Josephs, K A, Boeve, B F, Parisi, J E, Seeley, W W, Miller, B L, Karydas, A M, Rosen, H, van Swieten, J C, Dopper, E G P, Seelaar, H, Pijnenburg, Y A L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, A B, Hardy, J, and Momeni, P

Subjects
Genetics, 0303 health sciences, business.industry, nutritional and metabolic diseases, Single-nucleotide polymorphism, Genome-wide association study, Disease, medicine.disease, nervous system diseases, 3. Good health, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Immunology, Medicine, Corticobasal degeneration, Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association, Frontotemporal dementia
Abstract

BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Methods and findingsUsing large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs)jointlyassociated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA)region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci withinLRRK2(Leucine Rich Repeat Kinase 2), TBKBP1(TANK-binding kinase 1 Binding Protein 1), andPGBD5(PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within theHLAregion) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.ConclusionsWe show considerable immune-mediated genetic enrichment specifically in FTD, particularly within theHLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results