365 research outputs found
Social capital and willingness to participate in COVID-19 vaccine trials: an Italian case-control study
Background: What leads healthy people to enter in a volunteer register for clinical trials? This study aimed to investigate the relationship between the decision to volunteer in clinical trials for a COVID-19 vaccine and social capital, in
a sample of healthy volunteers in Italy. Since social capital is characterized by trust, reciprocity, and social and political
participation, we claim that it is key in leading individuals to actively take action to protect public health, and to take a
risk for the (potential) beneft not only of themselves but for the entire community.
Methods: This study was conducted through the administration of a questionnaire to healthy volunteers registered
for a phase 1 clinical trial for a COVID-19 vaccine in the Unit Research Centre of ASST-Monza, in September 2020. The
primary purpose of a phase 1 study is to evaluate the safety of a new drug candidate before it proceeds to further
clinical studies. To approximate a case–control study, we randomly matched the 318 respondents to healthy volunteers (cases) with 318 people randomly selected by Round 9 of the European Social Survey (controls), using three
variables, which we considered to be associated with the decision to volunteer: gender, age, and education level. To
execute this matching procedure, we used the “ccmatch” module in STATA.
Results: The fndings highlight the positive impact of social capital in the choice of healthy individuals to volunteer
in COVID-19 vaccine clinical trials. Controlling for possible confounding factors, some exemplary results show that
people with a high level of general trust have a greater likelihood of volunteering compared to people with low
trust (OR=2.75, CI=1.58–4.77); we also found that it is more probable that volunteers are people who have actively
taken action to improve things compared with people who have not (for individuals who did three or more actions:
OR=7.54, CI=4.10–13.86). People who reported voting (OR=3.91, CI=1.70–8.99) and participating in social activities more than other people of their age (OR=2.89, CI=1.82–4.60) showed a higher probability to volunteer.
Conclusions: Together with the adoption of urgent health measures in response to COVID-19, government policymakers should also promote social capital initiatives to encourage individuals to actively engage in actions aimed at
protecting collective health. Our fndings make an empirical contribution to the research on vaccines and its intersection with social behaviour, and they provide useful insights for policymakers to manage current and future disease
outbreaks and to enhance the enrolment in vaccine trials
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Metabolic gatekeeper function of B-lymphoid transcription factors.
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation
Fulvestrant and trastuzumab in patients with luminal HER2-positive advanced breast cancer (ABC): an Italian real-world experience (HERMIONE 9)
Purpose The most appropriate therapy for HR+/HER2-positive (HER2+) advanced breast cancer (ABC) is a matter of
debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them.
Methods The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR+/HER2+ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of
their routine treatment at 10 Italian Institutions.
Results Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous
treatments was 3 (range, 0–10) and F and T were administered as≥3rd line in 67 patients. Among the 86 evaluable patients,
6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥24 weeks with an overall CBR of 78.2%. At a median
follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No diference was observed
in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23
patients, respectively), neither considering the number of previous treatment lines (≤3 or<3).
Conclusion The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression
Understanding Factors Associated With Psychomotor Subtypes of Delirium in Older Inpatients With Dementia
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.Andre Franke and David Ellinghaus were supported by a grant from the German
Federal Ministry of Education and Research (01KI20197), Andre Franke, David
Ellinghaus and Frauke Degenhardt were supported by the Deutsche
Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic
Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal
Ministry of Education and Research (BMBF) within the framework of the
Computational Life Sciences funding concept (CompLS grant 031L0165). David
Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk
Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana
Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German
Research Foundation (DFG) through the Research Training Group 1743, "Genes,
Environment and Inflammation". This project was supported by a Covid-19 grant from
the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197).
Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione
primaria cardiovascolare primaria nella popolazione italiana; The European Union
(EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project
LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca
corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione
IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi
was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research
(Covid-Bank). This research was partly funded by a MIUR grant to the Department of
Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This
study makes use of data generated by the GCAT-Genomes for Life. Cohort study of
the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program /
Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026);
the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529).
Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en
Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional
(FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national
grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”).
Additional data included in this study was obtained in part by the COVICAT Study
Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19
Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià
and Sara Marsal were supported by the Spanish Ministry of Economy and
Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36).
Antonio Julià was also supported the by national grant PI17/00019 from the Acción
Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque
Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received
Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal
de Investigación (AEI, Spain) and the European Regional Development Fund
(FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán
and Douglas Maya Miles are supported by the “Spanish Ministry of Economy,
Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404,
PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian
government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed,
COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant
FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud.
Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health
(CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from
Research Council of Norway grant no 312780 during the conduct of the study. Dr.
Solligård: reports grants from Research Council of Norway grant no 312769. The
BioMaterialBank Nord is supported by the German Center for Lung Research (DZL),
Airway Research Center North (ARCN). The BioMaterialBank Nord is member of
popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants
from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne
Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases,
University of Cologne, Cologne, Germany. He is supported by the German Federal
Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the
German Federal Ministry of Research and Education and is funded by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's
Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded
by Technical University of Munich, Munich, Germany. Genotyping was performed by
the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM
Technology Centre, University of Helsinki. This work was supported by grants of the
Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland
and Lower Saxony. Kerstin U. Ludwig is supported by the German Research
Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the
Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported
by the Bavarian State Ministry for Science and Arts. Part of the genotyping was
supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA
BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative
Disease Research (JPND). Additional funding was derived from the German Research
Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is
supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH
state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist
Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision
Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf
are supported by the German Center for Infection Research (DZIF). Thorsen Brenner,
Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung
Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la
Cierva Incorporacion program, grant IJC2018-035131-I funded by
MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche
Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N
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PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL
Rings and Bricks: Expression of Cohesin Components is Dynamic during Development and Adult Life.
Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies.This work has been supported by Fondazione Cariplo, grant No. 2015-0783 to Valentina Massa, and by Fondazione Mariani (Como, Italy) to Angelo Selicorni
Clonal Evolution and Lack of BCR-ABL1 Mutations in Pediatric Ph+ ALL Patients Resistant/Refractory to Imatinib Treatment
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