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1. Differential gene expression analysis pipelines and bioinformatic tools for the identification of specific biomarkers: A review

Author

Diletta Rosati, Maria Palmieri, Giulia Brunelli, Andrea Morrione, Francesco Iannelli, Elisa Frullanti, and Antonio Giordano

Subjects
Differential gene expression analysis, Pathway enrichment, Bioinformatic analyses, Biomarkers, Biomarkers discovery, Biotechnology, TP248.13-248.65
Abstract

In recent years, the role of bioinformatics and computational biology together with omics techniques and transcriptomics has gained tremendous importance in biomedicine and healthcare, particularly for the identification of biomarkers for precision medicine and drug discovery. Differential gene expression (DGE) analysis is one of the most used techniques for RNA-sequencing (RNA-seq) data analysis. This tool, which is typically used in various RNA-seq data processing applications, allows the identification of differentially expressed genes across two or more sample sets. Functional enrichment analyses can then be performed to annotate and contextualize the resulting gene lists. These studies provide valuable information about disease-causing biological processes and can help in identifying molecular targets for novel therapies. This review focuses on differential gene expression (DGE) analysis pipelines and bioinformatic techniques commonly used to identify specific biomarkers and discuss the advantages and disadvantages of these techniques.

Published
2024
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4. Test Fonetico per la Prima Infanzia (TFPI): A New Instrument to Assess Italian Toddlers’ Phonetic Development

Author

Claudio Zmarich, Sabrina Bonichini, Marta Motterle, Maria Palmieri, Emanuela Sanfelici, and Serena Bonifacio

Subjects
phonetic development, percentage of consonants correct, phonetic inventories, articulation test, Phon, Language and Literature
Abstract

The purpose was to contribute to the validation of the TFPI, a new tool to assess the phonetic development of Italian-speaking children aged 18–47 months. Since currently norm-referenced instruments for Italian are lacking, the TFPI would fill this gap. We recruited 52 monolingual children aged 24–47 months with typical development. They were administered the complete TFPI, i.e., a naming task and repetition task; however, only their performances from the naming task were analyzed. The sessions were audio-recorded, in order to be later segmented and annotated in Praat, then manually transcribed with IPA. These data were then imported into Phon, an extremely suitable software for conducting analyses of phonological and speech data. We compiled the Phonetic Inventory (PhI) and calculated the Percentage of Consonants Correct (PCC) for each child, taking into consideration the allophones of Italian, in order to not compute them as errors. Both the PhI and the PCC improve with age, while intersubjective variability progressively decreases. Additionally, we investigated the age of the acquisition of each phone, since this domain lacks robust scientific data. Finally, our results align with previous findings, which proves the reliability and validity of the TFPI, and provides new information about the PCC, for which there are no reference values for the Italian language.

Published
2025
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6. Case report: PIK3CA somatic mutation leading to Klippel Trenaunay Syndrome and multiple tumors

Author

Viola Bianca Serio, Maria Palmieri, Simona Innamorato, Lorenzo Loberti, Chiara Fallerini, Francesca Ariani, Enrica Antolini, Jasmine Covarelli, Massimo Vaghi, Elisa Frullanti, Alessandra Renieri, and Anna Maria Pinto

Subjects
NGS-liquid biopsy, Klippel-Trenaunay Syndrome, squamous cell carcinoma adenocarcinoma, tailored therapy, case report, Genetics, QH426-470
Abstract

We report a case of Klippel Trenaunay Syndrome that was monitored both clinically and molecularly over a period of 9 years. A somatic mosaic mutation of PIK3CA (p(E545G)) was identified using both cfDNA NGS liquid biopsy and tissue biopsy. At the age of 56, due to intervening clonal mutations in PIK3CA background, she developed a squamous cell carcinoma in the right affected leg which was treated surgically. Nine years later, lung bilateral adenocarcinoma arose on PIK3CA mutated tissues supported by different clonal mutations. One year later, the patient died from metastases led by a new FGFR3 clone unresponsive to standard-of-care, immunotherapy-based. Our results highlight the presence of a molecular hallmark underlying neoplastic transformation that occurs upon an angiodysplastic process and support the view that PIK3CA mutated tissues must be treated as precancerous lesions. Importantly, they remark the effectiveness of combining cfDNA NGS liquid and tissue biopsies to monitor disease evolution as well as to identify aggressive clones targetable by tailored therapy, which is more efficient than conventional protocols.

Published
2023
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7. Diagnostic accuracy of circulating free DNA testing for the detection of KRAS mutations in non-small cell lung cancer: A systematic review and meta-analysis

Author

Maria Palmieri, Elisabetta Zulato, Sissel Gyrid Freim Wahl, Nicolas Guibert, and Elisa Frullanti

Subjects
cancer risk, diagnostic value, genetic biomarkers, single-nucleotide polymorphisms, liquid biopsy, Genetics, QH426-470
Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a GTPase that acts as a molecular switch for intracellular signal transduction, promoting cell growth and proliferation. Mutations in the KRAS gene represent important biomarkers for NSCLC targeted therapy. However, detection of KRAS mutations in tissues has shown some limitations. During the last years, analyses of circulating free DNA (cfDNA) has emerged as an alternative and minimally invasive, approach to investigate tumor molecular changes. Here, we assessed the diagnostic performance of cfDNA analysis, compared to tissues through a meta-analysis and systematic review of existing literature. From 561 candidate papers, we finally identified 40 studies, including 2,805 NSCLC patients. We extracted values relating to the number of true-positive, false-positive, false-negative, and true-negative. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, each with 95% CI, were calculated. A summary receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the overall diagnostic performance. The pooled sensitivity was 0.71 (95% CI 0.68–0.74) and the specificity was 0.93 (95% CI 0.92–0.94). The diagnostic odds ratio was 35.24 (95% CI 24.88–49.91) and the area under the curve was 0.92 (SE = 0.094). These results provide evidence that detection of KRAS mutation using cfDNA testing is of adequate diagnostic accuracy thus offering to the clinicians a new promising screening test for NSCLC patients.

Published
2022
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8. SELP Asp603Asn and severe thrombosis in COVID-19 males

Author

Chiara Fallerini, Sergio Daga, Elisa Benetti, Nicola Picchiotti, Kristina Zguro, Francesca Catapano, Virginia Baroni, Simone Lanini, Alessandro Bucalossi, Giuseppe Marotta, Francesca Colombo, Margherita Baldassarri, Francesca Fava, Giada Beligni, Laura Di Sarno, Diana Alaverdian, Maria Palmieri, Susanna Croci, Andrea M. Isidori, Simone Furini, Elisa Frullanti, GEN-COVID Multicenter Study, Alessandra Renieri, and Francesca Mari

Subjects
COVID-19, Thromboembolism, Thrombus, Venous thromboembolism, P-selectin, Anti-selectin P monoclonal antibodies, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G > A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54–3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53–3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41–7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.

Published
2021
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9. Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

Author

Maria Palmieri, Margherita Baldassarri, Francesca Fava, Alessandra Fabbiani, Elisa Gelli, Rossella Tita, Pamela Torre, Roberto Petrioli, Theodora Hadijstilianou, Daniela Galimberti, Elisa Cinotti, Carmelo Bengala, Marco Mandalà, Pietro Piu, Salvatora Tindara Miano, Ignazio Martellucci, Agnese Vannini, Anna Maria Pinto, Maria Antonietta Mencarelli, Stefania Marsili, Alessandra Renieri, and Elisa Frullanti

Subjects
cell‐free DNA, liquid biopsy, next‐generation sequencing, solid tumors, targeted‐therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). Conclusions Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

Published
2020
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10. Correction: SELP Asp603Asn and severe thrombosis in COVID-19 males

Author

Chiara Fallerini, Sergio Daga, Elisa Benetti, Nicola Picchiotti, Kristina Zguro, Francesca Catapano, Virginia Baroni, Simone Lanini, Alessandro Bucalossi, Giuseppe Marotta, Francesca Colombo, Margherita Baldassarri, Francesca Fava, Giada Beligni, Laura Di Sarno, Diana Alaverdian, Maria Palmieri, Susanna Croci, Andrea M. Isidori, Simone Furini, Elisa Frullanti, on behalf of GEN-COVID Multicenter Study, Alessandra Renieri, and Francesca Mari

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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11. Different Liquid Biopsies for the Management of Non-Small Cell Lung Cancer in the Mutational Oncology Era

Author

Maria Palmieri and Elisa Frullanti

Subjects
lung cancer, liquid biopsy, non-small cell lung carcinoma, Medicine
Abstract

In the last ten years, liquid biopsy has been slowly joining the traditional invasive techniques for the diagnosis and monitoring of tumors. Liquid biopsies allow easy repeated sampling of blood, reflect the tumor scenario, and make personalized therapy real for the patient. Liquid biopsies isolate and utilize different substrates present in patients’ body fluids such as circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc. One of the most-used solid cancers in the development of the non-invasive liquid biopsy approach that has benefited from scientific advances is non-small cell lung cancer (NSCLC). Using liquid biopsy, it is possible to have more details on NSCLC staging, progression, heterogeneity, gene mutations and clonal evolution, etc., basing the treatment on precision medicine as well as on the screening of markers for therapeutic resistance. With this review, the authors propose a complete and current overview of all different liquid biopsies available to date, to understand how much has been carried out and how much remains to be completed for a better characterization of NSCLC.

Published
2023
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12. Cell-free DNA next-generation sequencing liquid biopsy as a new revolutionary approach for arteriovenous malformation

Author

Maria Palmieri, MS, Aurora Currò, MD, Andrea Tommasi, MD, Laura Di Sarno, MS, Gabriella Doddato, MS, Margheria Baldassarri, MD, Elisa Frullanti, MS, Ann Rita Giliberti, MS, Chiara Fallerini, MS, Angelo Spinazzola, MD, Anna Maria Pinto, MD, PhD, Alessandra Renieri, MD, PhD, and Massimo Vaghi, MD

Subjects
Arteriovenous malformation, Liquid biopsy, cf-DNA, KRAS mutation, Noninvasive technique, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Objective: Somatic mosaicism of KRAS gene is currently recognized as the only established molecular basis of arteriovenous malformations (AVM). However, given the limitations of the current technologies, KRAS somatic mutations are detected only in a limited proportion of AVMs and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next-generation sequencing liquid biopsy using cell-free DNA (cfDNA) has emerged as an innovative noninvasive approach for early detection and monitoring of cancer. This approach overcomes the space-time profile constraint of tissue biopsies opens a new scenario for vascular malformations owing to somatic mosaicism. Here, we propose a new approach as a fast noninvasive reliable tool in order to investigate the cfDNA coming from the AVMs. Methods: A group of five patients suffering from AVM were selected. Blood samples from peripheral vein and efferent vein from vascular malformation were collected and cfDNA was extracted. The cfDNA libraries were performed using Oncomine Pan-Cancer Cell-Free Assay. We used Ion Proton for sequencing and Ion Reporter Software for analysis (Life Technologies, Carlsbad, Calif). Results: In all cases, either G12D or G12V mutations in KRAS were identified. The mutational load was higher in the efferent vein than in peripheral blood, confirming the causative role of the identified mutation at a somatic level. Conclusions: We demonstrate that cfDNA next-generation sequencing liquid biopsy is able to identify the KRAS mutation detected in affected tissues. Moreover, we have shown that blood sample withdrawal at the lesion site increases variant allele frequency with an order of magnitude above the limit of detection (usually 0.05%), decreasing the risk of a false negative. Finally, the noninvasiveness of the method avoids any risk of bleeding, being easily performed also in children. We propose this technique as the method of choice to better investigate AVMs and consequently to identify the therapy tailored to the genetic defect. Clinical Relevance: This article highlights the importance of using liquid biopsy as a new method to investigate the molecular profile of AVMs. In view of the frequent inaccessibility of vascular tissues owing to the invasiveness of solid biopsy and the relative high incidence of biopsies with low diagnostic power, here we evaluated the efficacy of detecting cfDNA fragments released into the bloodstream from the affected tissue cells. Through a simple blood draw from the efferent vein at the vascular malformation site, the liquid biopsy allowed us to identify KRAS pathogenic mutations piloting a personalized therapeutic approach and opening a new scenario for new therapeutic strategies.

Published
2020
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13. PIK3CA-CDKN2A clonal evolution in metastatic breast cancer and multiple points cell-free DNA analysis

Author

Maria Palmieri, Margherita Baldassarri, Francesca Fava, Alessandra Fabbiani, Giuseppe Maria Campennì, Maria Antonietta Mencarelli, Rossella Tita, Stefania Marsili, Alessandra Renieri, and Elisa Frullanti

Subjects
PIK3CA-CDKN2A, cfDNA, Liquid biopsy, Deep-next generation sequencing, Targeted-therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Background Daily experience tells us that breast cancer can be controlled using standard protocols up to the advent of a relapse. Now new frontiers in precision medicine like liquid biopsy of cell free DNA (cfDNA) give us the possibility to understand cancer evolution and pick up the key mutation on specific cancer driver gene. However, tight schedule of standardized protocol may impair the use of personalized experimental drugs in a timely therapeutic window. Main body Here, using a combination of deep next generation sequencing and cfDNA liquid biopsy, we demonstrated that it is possible to monitor cancer relapse over time. We showed for the first time the exact correspondence from the increasing clonal expansion and clinical worsening of metastatic breast cancer. Conclusion Thanks to liquid biopsy may be possible to introduce new experimental drugs in the correct therapeutic window which would lead in the near future to an effective treatment which otherwise remains challenging.

Published
2019
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14. Galdieria sulphuraria ACUF427 Freeze-Dried Biomass as Novel Biosorbent for Rare Earth Elements

Author

Maria Palmieri, Manuela Iovinella, Seth J. Davis, Maria Rosa di Cicco, Carmine Lubritto, Marco Race, Stefania Papa, Massimiliano Fabbricino, and Claudia Ciniglia

Subjects
Galdieria sulphuraria, biosorption, rare earth, Biology (General), QH301-705.5
Abstract

Rare earth elements (REEs) are essential components of modern technologies and are often challenging to acquire from natural resources. The demand for REEs is so high that there is a clear need to develop efficient and environmentally-friendly recycling methods. In the present study, freeze-dried cells of the extremophile Galdieria sulphuraria were employed to recover yttrium, cerium, europium, and terbium from quaternary-metal aqueous solutions. The biosorption capacity of G. sulphuraria freeze-dried algal biomass was tested at different pHs, contact times, and biosorbent dosages. All rare earths were biosorbed in a more efficient way by the lowest dose of biosorbent, at pH 4.5, within 30 min; the highest removal rate of cerium was recorded at acidic pH (2.5) and after a longer contact time, i.e., 360 min. This study confirms the potential of freeze-dried cells of G. sulphuraria as innovative ecological biosorbents in technological applications for sustainable recycling of metals from e-waste and wastewater.

Published
2022
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15. Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author

Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, and Francesca Ariani

Subjects
BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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16. Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author

Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, Francesca Ariani, Alessandro Neri, Donato Casella, Andrea Bernini, Stefania Marsili, Roberto Petrioli, Salvatora Tindara Miano, Alessandra Pascucci, Ignazio Martellucci, Monica Crociani, Marta Vannini, Federica Fantozzi, Andrea Stella, Alessia Carmela Tripodi, Angelamaria Giusti, Alfonso Fausto, Lucia Mantovani, and Francesca Belardi

Subjects
BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.

Published
2021
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17. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Author

Chiara Fallerini, Sergio Daga, Stefania Mantovani, Elisa Benetti, Nicola Picchiotti, Daniela Francisci, Francesco Paciosi, Elisabetta Schiaroli, Margherita Baldassarri, Francesca Fava, Maria Palmieri, Serena Ludovisi, Francesco Castelli, Eugenia Quiros-Roldan, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Maria Bandini, Ottavia Spiga, Katia Capitani, Simone Furini, Francesca Mari, GEN-COVID Multicenter Study, Alessandra Renieri, Mario U Mondelli, and Elisa Frullanti

Subjects
TLR7, COVID-19, LASSO Logistic Regression Analysis, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (

Published
2021
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18. RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report

Author

Elisa Gelli, Chiara Fallerini, Floriana Valentino, Annarita Giliberti, Francesca Castiglione, Lucrezia Laschi, Maria Palmieri, Alessandra Fabbiani, Rossella Tita, Maria Antonietta Mencarelli, Alessandra Renieri, and Francesca Ariani

Subjects
RB1, hypomorphic variant, yolk sac tumor, ovarian cancer, tumor predisposition, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.

Published
2020
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19. Bioremoval of Yttrium (III), Cerium (III), Europium (III), and Terbium (III) from Single and Quaternary Aqueous Solutions Using the Extremophile Galdieria sulphuraria (Galdieriaceae, Rhodophyta)

Author

Manuela Iovinella, Francesco Lombardo, Claudia Ciniglia, Maria Palmieri, Maria Rosa di Cicco, Marco Trifuoggi, Marco Race, Carla Manfredi, Carmine Lubritto, Massimiliano Fabbricino, Mario De Stefano, and Seth J. Davis

Subjects
recycling, rare earth elements, extremophile, G. sulphuraria, bioremoval, pH, Botany, QK1-989
Abstract

The lanthanides are among the rare earth elements (REEs), which are indispensable constituents of modern technologies and are often challenging to acquire from natural resources. The demand for REEs is so high that there is a clear need to develop efficient and environmentally-friendly recycling methods. In the present study, living cells of the extremophile Galdieria sulphuraria were used to remove four REEs, Yttrium, Cerium, Europium, and Terbium, from single- and quaternary-metal aqueous solutions. Two different strains, SAG 107.79 and ACUF 427, were exposed to solutions buffered at pH 2.5, 3.5, 4.5, and 5.5. Our data demonstrated that the removal performances were strain and pH dependent for all metal ions. At lower pH, ACUF 427 outperformed SAG 107.79 considerably. By increasing the pH of the solutions, there was a significant surge in the aqueous removal performance of both strains. The same trend was highlighted using quaternary-metal solutions, even if the quantities of metal removed were significantly lower. The present study provided the first insight into the comparative removal capacity of the Galdieria sulphuraria strains. The choice of the appropriate operational conditions such as the pH of the metal solutions is an essential step in developing efficient, rapid, and straightforward biological methods for recycling REEs.

Published
2022
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20. Cyanidiophyceae (Rhodophyta) Tolerance to Precious Metals: Metabolic Response to Palladium and Gold

Author

Maria Sirakov, Maria Palmieri, Manuela Iovinella, Seth J. Davis, Milena Petriccione, Maria Rosa di Cicco, Mario De Stefano, and Claudia Ciniglia

Subjects
metal tolerance, Galdieria sulphuraria, precious metals, metabolic response, Botany, QK1-989
Abstract

Polyextremophilic red algae, which belong to the class Cyanidiophyceae, are adapted to live in geothermal and volcanic sites. These sites often have very high concentrations of heavy and precious metals. In this study, we assessed the capacity of three strains of Galdieria (G. maxima, G. sulphuraria, and G. phlegrea) and one strain of Cyanidiumcaldarium to tolerate different concentrations of precious metals, such as palladium (Cl4K2Pd) and gold (AuCl4K) by monitoring algal growths in cultures exposed to metals, and we investigated the algae potential oxidative stress induced by the metals. This work provides further understanding of metals responses in the Cyanidiophyceae, as this taxonomic class is developed as a biological refinement tool.

Published
2021
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21. Extremophilic Microalgae Galdieria Gen. for Urban Wastewater Treatment: Current State, the Case of 'POWER' System, and Future Prospects

Author

Maria Rosa di Cicco, Manuela Iovinella, Maria Palmieri, Carmine Lubritto, and Claudia Ciniglia

Subjects
microalgae cultivation, extremophile, Galdieria, phlegrea, sulphuraria, photobioreactor, Botany, QK1-989
Abstract

Over the past decades, wastewater research has increasingly focused on the use of microalgae as a tool to remove contaminants, entrapping nutrients, and whose biomass could provide both material and energy resources. This review covers the advances in the emerging research on the use in wastewater sector of thermoacidophilic, low-lipid microalgae of the genus Galdieria, which exhibit high content of protein, reserve carbohydrates, and other potentially extractable high-value compounds. The natural tolerance of Galdieria for high toxic environments and hot climates recently made it a key player in a single-step process for municipal wastewater treatment, biomass cultivation and production of energetic compounds using hydrothermal liquefaction. In this system developed in New Mexico, Galdieria proved to be a highly performing organism, able to restore the composition of the effluent to the standards required by the current legislation for the discharge of treated wastewater. Future research efforts should focus on the implementation, in the context of wastewater treatment, of more energetically efficient cultivation systems, potentially capable of generating water with increasingly higher purity levels.

Published
2021
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23. Liquid Biopsy: A New Strategy for Future Directions in Lung Cancer Treatment

Author

Maria Palmieri and Elisa Frullanti

Abstract

The gold standard for cancer diagnosis has always been based on radiological imaging followed by surgical tissue biopsies for molecular testing and pathological examination and surgical resection to remove the tumoral mass when possible. However, the resulting information is a limited snapshot in space and time, which poorly reflects clonal heterogeneity or tumor evolution and metastasis. Over a decade since its inception, the ability to use non-invasive methods such as a liquid biopsy to analyze tumor biomarkers has transformed the vision of future cancer care into a better patient experience thanks to real-time monitoring and early diagnosis. The liquid biopsy essay is an effective tool for detecting cancers at an early stage, when there are very few tumor-derived materials circulating in the bloodstream, being a very sensitive technique. For this reason, liquid biopsy is particularly suitable for early-stage diagnosis (stage I or II) of lung cancer whose diagnosis often occurs in the final stages of the disease as well as monitoring cancer progression and driving target therapies.

Published
2023

24. Le reportage de voyage chez Gadda, Linati, Savinio et Bacchelli

Author

Giovanni Maria Palmieri

Subjects
Gadda (Carlo Emilio), Linati (Carlo), Savinio (Alberto), Bacchelli (Riccardo), reportage, voyage, Language and Literature, French literature - Italian literature - Spanish literature - Portuguese literature, PQ1-3999
Abstract

Au cours du XXe siècle le reportage de voyage, sous-genre du reportage tout court, se dégage complètement de la tradition de la travel literature et prend des caractéristiques particulières. L’article procède à une comparaison entre les reportages de voyage de Gadda et ceux de Carlo Linati, d’Alberto Savinio et de Riccardo Bacchelli, trois auteurs estimés par Gadda et qu’à l’exception de Savinio il avait connus personnellement.

Published
2014
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25. MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy

Author

Alessandra Renieri, Margherita Baldassarri, Annarita Giliberti, Laura Di Sarno, Elisa Frullanti, Chiara Fallerini, Gabriella Doddato, Andrea Tommasi, Aldo Arzini, Aurora Currò, Anna Maria Pinto, Massimo Vaghi, and Maria Palmieri

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Vascular Malformations, Somatic cell, DNA Mutational Analysis, 030204 cardiovascular system & hematology, medicine.disease_cause, Risk Assessment, Vascular anomaly, Noninvasive technique, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Predictive Value of Tests, Risk Factors, medicine, Activating MET Mutation, Humans, Genetic Predisposition to Disease, Prospective Studies, 030212 general & internal medicine, cfDNA, Liquid biopsy, Genetic Association Studies, Mutation, Lymphatic Abnormalities, business.industry, Vascular malformation, Lymphovenous malformation, MET mutation, Liquid Biopsy, High-Throughput Nucleotide Sequencing, Middle Aged, Proto-Oncogene Proteins c-met, medicine.disease, Phenotype, Lymphatic system, Italy, Female, Surgery, Cardiology and Cardiovascular Medicine, business, Cell-Free Nucleic Acids
Abstract

Objective Germline mutations of either the endothelial cell-specific tyrosine kinase receptor TIE2 or the glomulin (GLMN) gene are responsible for rare inherited venous malformations. Both genes affect the hepatocyte growth factor receptor c-Met, inducing vascular smooth muscle cell migration. Germline mutations of hepatocyte growth factor are responsible for lymphatic malformations, leading to lymphedema. The molecular alteration leading to the abnormal mixed vascular anomaly defined as lymphovenous malformation has remained unknown. Methods A group of 4 patients with lymphovenous malformations were selected. Plasma was obtained from both peripheral and efferent vein samples at the vascular malformation site for cell-free DNA extraction. When possible, we analyzed tissue biopsy samples from the vascular lesion. Results We have demonstrated that in all four patients, an activating MET mutation was present. In three of the four patients, the same pathogenic activating mutation, T1010I, was identified. The mutation was found at the tissue level for the patient with tissue samples available, confirming its causative role in the lymphovenous malformations. Conclusions In the present study, we have demonstrated that cell-free DNA next generation sequencing liquid biopsy is able to identify the MET mutations in affected tissues. Although a wider cohort of patients is necessary to confirm its causative role in lymphovenous malformations, these data suggest that lymphovenous malformations could result from postzygotic somatic mutations in genes that are key regulators of lymphatic development. The noninvasiveness of the method avoids any risk of bleeding and can be easily performed in children. We are confident that the present pioneering results have provided a viable alternative in the future for lymphovenous malformation diagnosis, allowing for subsequent therapy tailored to the genetic defect.

Published
2021
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26. Surface and Electrochemical Characterization of a New Layered GC/Betaine/Pt Electrode and Investigation on its Performance as a Sensor for two B Complex Vitamins, B1 and B6: Preliminary Results

Author

Donatella Coviello, Fausto Langerame, Maria Palmieri, Anna Maria Salvi, Rosanna Ciriello, Giuliana Bianco, Antonio Guerrieri, and Michela Contursi

Subjects
Pt electrode, chemistry.chemical_compound, B vitamins, Materials science, Betaine, chemistry, Inorganic chemistry, Electrochemistry, Cyclic voltammetry, Analytical Chemistry, Characterization (materials science)
Published
2020
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27. Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy

Author

Viola Bianca Serio, Maria Palmieri, Lorenzo Loberti, Stefania Granata, Chiara Fallerini, Massimo Vaghi, Alessandra Renieri, and Anna Maria Pinto

Subjects
NGS-liquid biopsy, arteriovenous malformations, lymphovenous malformations, venous malformations, tailored therapy, General Medicine
Abstract

Several different nosological classifications have been used over time for vascular malformations (VMs) since clinical and pathological signs are largely overlapping. In a large proportion of cases, VMs are generated by somatic mosaicism in key genes, belonging to a few different molecular pathways. Therefore, molecular characterization may help in the understanding of the biological mechanisms related to the development of pathology. Tissue biopsy is not routinely included in the diagnostic path because of the need for fresh tissue specimens and the risk of bleeding. Bypassing the need for bioptic samples, we took advantage of the possibility of isolating cell-free DNA likely released by the affected tissues, to molecularly characterize 53 patients by cfDNA-NGS liquid biopsy. We found a good match between the identified variant and the clinical presentation. PIK3CA variants were found in 67% of Klippel Trenaunay Syndrome individuals; KRAS variants in 60% of arteriovenous malformations; MET was mutated in 75% of lymphovenous malformations. Our results demonstrate the power of cfDNA-NGS liquid biopsy in VMs clinical classification, diagnosis, and treatment. Indeed, tailored repurposing of pre-existing cancer drugs, such as PIK3CA, KRAS, and MET inhibitors, can be envisaged as adjuvant treatment, in addition to surgery and/or endovascular treatment, in the above-defined VMs categories, respectively.

Published
2022

28. The ChoCO-W prospective observational global study: does COVID-19 increase gangrenous cholecystitis?

Author

Azamat, İbrahim (ORCID 0000-0002-1190-1803 & YÖK ID 188598); Omarov, Nail; Uymaz, Derya Salim, De Simone, Belinda; Abu-Zidan, Fikri M.; Chouillard, Elie; Di Saverio, Salomone; Sartelli, Massimo; Podda, Mauro; Gomes, Carlos Augusto; Moore, Ernest E.; Moug, Susan J.; Ansaloni, Luca; Kluger, Yoram; Coccolini, Federico; Landaluce-Olavarria, Aitor; Estraviz-Mateos, Begona; Uriguen-Etxeberria, Ana; Giordano, Alessio; Luna, Alfonso Palmieri; Amin, Luz Adriana Hernandez; Hernandez, Adriana Maria Palmieri; Shabana, Amanda; Dzulkarnaen, Zakaria Andee; Othman, Muhammad Asyraf; Sani, Mohamad Ikhwan; Balla, Andrea; Scaramuzzo, Rosa; Lepiane, Pasquale; Bottari, Andrea; Staderini, Fabio; Cianchi, Fabio; Cavallaro, Andrea; Zanghi, Antonio; Cappellani, Alessandro; Campagnacci, Roberto; Maurizi, Angela; Martinotti, Mario; Ruggieri, Annamaria; Jusoh, Asri Che; Rahman, Karim Abdul; Zulkifli, Anis Suraya M.; Petronio, Barbara; Matias-Garcia, Belen; Quiroga-Valcarcel, Ana; Mendoza-Moreno, Fernando; Atanasov, Boyko; Campanile, Fabio Cesare; Vecchioni, Ilaria; Cardinali, Luca; Travaglini, Grazia; Sebastiani, Elisa; Chooklin, Serge; Chuklin, Serhii; Cianci, Pasquale; Restini, Enrico; Capuzzolo, Sabino; Curro, Giuseppe; Filippo, Rosalinda; Rispoli, Michele; Aparicio-Sanchez, Daniel; Munoz-Cruzado, Virginia Duran; Barbeito, Sandra Dios; Delibegovic, Samir; Kesetovic, Amar; Sasia, Diego; Borghi, Felice; Giraudo, Giorgio; Visconti, Diego; Doria, Emanuele; Santarelli, Mauro; Luppi, Davide; Bonilauri, Stefano; Grossi, Ugo; Zanus, Giacomo; Sartori, Alberto; Piatto, Giacomo; De Luca, Maurizio; Vita, Domenico; Conti, Luigi; Capelli, Patrizio; Cattaneo, Gaetano Maria; Marinis, Athanasios; Vederaki, Styliani-Aikaterini; Bayrak, Mehmet; Altintas, Yasemin; Uzunoglu, Mustafa Yener; Demirbas, Iskender Eren; Altinel, Yuksel; Meric, Serhat; Aktimur, Yunus Emre; Lostoridis, Eftychios; Nagorni, Eleni-Aikaterini; Pujante, Antonio; Anania, Gabriele; Bombardini, Cristina; Bagolini, Francesco; Gonullu, Emre; Mantoglu, Baris; Capoglu, Recayi; Cappato, Stefano; Muzio, Elena; Colak, Elif; Polat, Suleyman; Koy, Koç University Hospital, School of Medicine, Azamat, İbrahim (ORCID 0000-0002-1190-1803 & YÖK ID 188598); Omarov, Nail; Uymaz, Derya Salim, De Simone, Belinda; Abu-Zidan, Fikri M.; Chouillard, Elie; Di Saverio, Salomone; Sartelli, Massimo; Podda, Mauro; Gomes, Carlos Augusto; Moore, Ernest E.; Moug, Susan J.; Ansaloni, Luca; Kluger, Yoram; Coccolini, Federico; Landaluce-Olavarria, Aitor; Estraviz-Mateos, Begona; Uriguen-Etxeberria, Ana; Giordano, Alessio; Luna, Alfonso Palmieri; Amin, Luz Adriana Hernandez; Hernandez, Adriana Maria Palmieri; Shabana, Amanda; Dzulkarnaen, Zakaria Andee; Othman, Muhammad Asyraf; Sani, Mohamad Ikhwan; Balla, Andrea; Scaramuzzo, Rosa; Lepiane, Pasquale; Bottari, Andrea; Staderini, Fabio; Cianchi, Fabio; Cavallaro, Andrea; Zanghi, Antonio; Cappellani, Alessandro; Campagnacci, Roberto; Maurizi, Angela; Martinotti, Mario; Ruggieri, Annamaria; Jusoh, Asri Che; Rahman, Karim Abdul; Zulkifli, Anis Suraya M.; Petronio, Barbara; Matias-Garcia, Belen; Quiroga-Valcarcel, Ana; Mendoza-Moreno, Fernando; Atanasov, Boyko; Campanile, Fabio Cesare; Vecchioni, Ilaria; Cardinali, Luca; Travaglini, Grazia; Sebastiani, Elisa; Chooklin, Serge; Chuklin, Serhii; Cianci, Pasquale; Restini, Enrico; Capuzzolo, Sabino; Curro, Giuseppe; Filippo, Rosalinda; Rispoli, Michele; Aparicio-Sanchez, Daniel; Munoz-Cruzado, Virginia Duran; Barbeito, Sandra Dios; Delibegovic, Samir; Kesetovic, Amar; Sasia, Diego; Borghi, Felice; Giraudo, Giorgio; Visconti, Diego; Doria, Emanuele; Santarelli, Mauro; Luppi, Davide; Bonilauri, Stefano; Grossi, Ugo; Zanus, Giacomo; Sartori, Alberto; Piatto, Giacomo; De Luca, Maurizio; Vita, Domenico; Conti, Luigi; Capelli, Patrizio; Cattaneo, Gaetano Maria; Marinis, Athanasios; Vederaki, Styliani-Aikaterini; Bayrak, Mehmet; Altintas, Yasemin; Uzunoglu, Mustafa Yener; Demirbas, Iskender Eren; Altinel, Yuksel; Meric, Serhat; Aktimur, Yunus Emre; Lostoridis, Eftychios; Nagorni, Eleni-Aikaterini; Pujante, Antonio; Anania, Gabriele; Bombardini, Cristina; Bagolini, Francesco; Gonullu, Emre; Mantoglu, Baris; Capoglu, Recayi; Cappato, Stefano; Muzio, Elena; Colak, Elif; Polat, Suleyman; Koy, Koç University Hospital, and School of Medicine

Abstract

Background: the incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not. Methods: data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not. Results: a total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p < 0.0001), diabetes (p < 0.0001), and severe chronic obstructive airway disease (p = 0.005) were significantly more frequent in the COVID-19 group. Markers of sepsis severity including ARDS (p < 0.0001), PIPAS score (p < 0.0001), WSES sepsis score (p < 0.0001), qSOFA (p < 0.0001), and Tokyo classification of severity of acute cholecystitis (p < 0.0001) were significantly higher in the COVID-19 group. The COVID-19 group had significantly higher postoperative complications (32.2% compared with 11.7%, p < 0.0001), longer mean hospital stay (13.21 compared with 6.51 days, p < 0.0001), and mortality rate (13.4% compared with 1.7%, p < 0.0001). The incidence of gangrenous cholecystitis was doubled in the COVID-19 group (40.7% compared with 22.3%). The mean wall thickness of the gallbladder was significantly higher in the COVID-19 group [6.32 (SD: 2.44) mm compared with 5.4 (SD: 3.45) mm; p < 0.0001]. Conclusions, NA

Published
2022

29. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, Serena Ludovisi, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, and Serena Ludovisi

Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

Published
2022

30. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco GEN-COVID Multicenter Study: Francesca Mari, Sergio, Daga, Elisa, Benetti, Mirella, Bruttini, Maria, Palmieri, Susanna, Croci, Sara, Amitrano, Ilaria, Meloni, Elisa, Frullanti, Gabriella, Doddato, Mirjam, Lista, Giada, Beligni, Floriana, Valentino, Kristina, Zguro, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca, Ariani, Laura Di Sarno, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella D'Arminio Monforte, Federica Gaia Miraglia, Raffaele, Bruno, Marco, Vecchia, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Umberto, Zuccon, Lucia, Vietri, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Roberto, Menè, Marta, Colaneri, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Stefania, Mantovani, Mario, U Mondelli, Serena, Ludovisi, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, nbsp, Multicenter Study, GEN-COVID, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, and Ludovisi, S

Subjects
Genetics, Coronavirus disease 2019 (COVID-19), Host (biology), COVID-19, Medicine (miscellaneous), Settore BIO/11 - Biologia Molecolare, Biology, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Whole Exome Sequencing, General Biochemistry, Genetics and Molecular Biology, machine learning, Phenotype, Exome Sequencing, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, General Agricultural and Biological Sciences, COVID, Human
Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from tree-based models allowed to identify a handful of 16 variants with highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.

Published
2022
Full Text
View/download PDF

35. The polymorphism L412F in

Author

Susanna, Croci, Mary Anna, Venneri, Stefania, Mantovani, Chiara, Fallerini, Elisa, Benetti, Nicola, Picchiotti, Federica, Campolo, Francesco, Imperatore, Maria, Palmieri, Sergio, Daga, Chiara, Gabbi, Francesca, Montagnani, Giada, Beligni, Ticiana D J, Farias, Miriam Lucia, Carriero, Laura, Di Sarno, Diana, Alaverdian, Sigrid, Aslaksen, Maria Vittoria, Cubellis, Ottavia, Spiga, Margherita, Baldassarri, Francesca, Fava, Paul J, Norman, Elisa, Frullanti, Andrea M, Isidori, Antonio, Amoroso, Francesca, Mari, Simone, Furini, Mario U, Mondelli, Gen-Covid Multicenter Study, Mario, Chiariello, Alessandra, Renieri, and Ilaria, Meloni

Subjects
Male, HEK293 Cells, SARS-CoV-2, Autophagy, COVID-19, Humans, Polymorphism, Single Nucleotide, Severity of Illness Index, Biomarkers, Hydroxychloroquine, Toll-Like Receptor 3
Abstract

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3

Published
2021

36. Extremophilic Microalgae

Author

Maria Rosa, di Cicco, Manuela, Iovinella, Maria, Palmieri, Carmine, Lubritto, and Claudia, Ciniglia

Subjects
pollutants removal, microalgae cultivation, photobioreactor, sulphuraria, phlegrea, urban wastewater, Review, extremophile, Galdieria
Abstract

Over the past decades, wastewater research has increasingly focused on the use of microalgae as a tool to remove contaminants, entrapping nutrients, and whose biomass could provide both material and energy resources. This review covers the advances in the emerging research on the use in wastewater sector of thermoacidophilic, low-lipid microalgae of the genus Galdieria, which exhibit high content of protein, reserve carbohydrates, and other potentially extractable high-value compounds. The natural tolerance of Galdieria for high toxic environments and hot climates recently made it a key player in a single-step process for municipal wastewater treatment, biomass cultivation and production of energetic compounds using hydrothermal liquefaction. In this system developed in New Mexico, Galdieria proved to be a highly performing organism, able to restore the composition of the effluent to the standards required by the current legislation for the discharge of treated wastewater. Future research efforts should focus on the implementation, in the context of wastewater treatment, of more energetically efficient cultivation systems, potentially capable of generating water with increasingly higher purity levels.

Published
2021

37. Cyanidiophyceae (Rhodophyta) Tolerance to Precious Metals: Metabolic Response to Palladium and Gold

Author

Mario De Stefano, Claudia Ciniglia, Maria Sirakov, Milena Petriccione, Maria Rosa di Cicco, Manuela Iovinella, Seth J. Davis, Maria Palmieri, Sirakov, Maria, Palmieri, Maria, Iovinella, Manuela, J Davis, Seth, Petriccione, Milena, di CICCO, Maria Rosa, DE STEFANO, Mario, and Ciniglia, Claudia

Subjects
metal tolerance, chemistry.chemical_element, Plant Science, Red algae, 010501 environmental sciences, metabolic response, 01 natural sciences, Galdieria sulphuraria, 03 medical and health sciences, Algae, Cyanidiophyceae, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Ecology, biology, Communication, Botany, precious metals, biology.organism_classification, precious metal, chemistry, Environmental chemistry, QK1-989, Palladium
Abstract

Polyextremophilic red algae, which belong to the class Cyanidiophyceae, are adapted to live in geothermal and volcanic sites. These sites often have very high concentrations of heavy and precious metals. In this study, we assessed the capacity of three strains of Galdieria (G. maxima, G. sulphuraria, and G. phlegrea) and one strain of Cyanidiumcaldarium to tolerate different concentrations of precious metals, such as palladium (Cl4K2Pd) and gold (AuCl4K) by monitoring algal growths in cultures exposed to metals, and we investigated the algae potential oxidative stress induced by the metals. This work provides further understanding of metals responses in the Cyanidiophyceae, as this taxonomic class is developed as a biological refinement tool.

Published
2021

38. Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

Author

Margherita Baldassarri, Francesca Fava, Chiara Fallerini, Sergio Daga, Elisa Benetti, Kristina Zguro, Sara Amitrano, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Giada Beligni, Nicola Iuso, Francesco Castelli, Eugenia Quiros-Roldan, Mario Umberto Mondelli, Rosalba Miceli, Elisa Frullanti, Simone Furini, Francesca Mari, Alessandra Renieri, Chiara Gabbi, and on behalf of the GEN-COVID Multicenter Study

Subjects
medicine.medical_specialty, Medicine (miscellaneous), Asymptomatic, Cystic fibrosis, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, CFTR, CF carrier screening, Exome sequencing, 030304 developmental biology, 0303 health sciences, Respiratory tract infections, business.industry, Hazard ratio, COVID-19, medicine.disease, Host genetics, host genetics, Relative risk, Cohort, Medicine, medicine.symptom, business, Cohort study
Abstract

The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene—CF-carriers—are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with COVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p &lt, 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p &lt, 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p &lt, 0.05) and their hazard ratio of death at day 14 was 3.10 (p &lt, 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.

Published
2021

39. The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

Author

Francesco Imperatore, Sergio Daga, Mary Anna Venneri, Laura Di Sarno, Maria Vittoria Cubellis, Francesca Montagnani, Sigrid Aslaksen, Alessandra Renieri, Paul Norman, Simone Furini, Stefania Mantovani, Mario Chiariello, Mario U. Mondelli, Giada Beligni, Gen-Covid Multicenter Study, Ilaria Meloni, Elisa Benetti, Ottavia Spiga, Federica Campolo, Margherita Baldassarri, Diana Alaverdian, Nicola Picchiotti, Francesca Fava, Chiara Fallerini, Andrea M. Isidori, Elisa Frullanti, Antonio Amoroso, Miriam Lucia Carriero, Francesca Mari, Maria Palmieri, Susanna Croci, Ticiana Della Justina Farias, and C. Gabbi

Subjects
Agonist, medicine.drug_class, business.industry, Autophagy, HEK 293 cells, Hydroxychloroquine, Transfection, Plasmid, Polymorphism (computer science), TLR3, Immunology, medicine, business, medicine.drug
Abstract

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired autophagy and reduced TNFα production was demonstrated in HEK293 cells transfected with TLR3-L412F plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (P=0.038). An increased frequency of autoimmune disorders as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways.

Published
2021
Full Text
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40. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Published
2022
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41. Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Author

Diego Ripamonti, Sandro Panese, Agnese Verzuri, Giancarlo Bosio, Francesco Castelli, Leonardo Croci, Maurizio Spagnesi, Sergio Daga, Massimiliano Fabbiani, Barbara Rossetti, Silvia Cappelli, Giada Beligni, Gabriella Coiro, Antonio Di Biagio, Domenico A Coviello, Massimo Girardis, Pamela Raggi, Roberta Russo, Federico Franchi, Matteo Bassetti, Stefano Baratti, Gianfranco Parati, Francesca Montagnani, Marco Rizzi, Eugenia Quiros-Roldan, Francesca Fava, Tiziana Bachetti, Agostino Riva, Filippo Aucella, Francesca Gatti, Anna Canaccini, Anna Maria Pinto, Sandro Mancarella, Alessandra Renieri, Arianna Gabrieli, Mario Chiariello, Rossella Tita, Luca Guidelli, Sophie Venturelli, Ilaria Meloni, Luisa Tavecchia, Marta Corridi, Susanna Croci, Francesca Mari, Pierpaolo Parravicini, Andrea Tommasi, Carmelo Piscopo, Tullio Trotta, Miriana d'Alessandro, Maria Antonietta Mencarelli, Cristina Mussini, Simone Furini, Alessandra Vergori, Gen-Covid Multicenter Study, Margherita Baldassarri, Daniela Francisci, Giuseppe Fiorentino, Simona Sarzi-Braga, Mirella Bruttini, Sabino Scolletta, Mario Capasso, Melania Degli Antoni, Serafina Valente, Alice Donati, Maria Antonietta Mazzei, Maurizio Bussotti, Chiara Fallerini, Laura Di Sarno, Federico Anedda, Davide Romani, Katia Capitani, Gian Piero Caldarelli, Elisa Frullanti, Caterina Lo Rizzo, Bruno Frediani, Marco Castori, Arianna Emiliozzi, Andrea Cossarizza, Elena Desanctis, Luca Cantarini, Cesira Nencioni, Ottavia Spiga, Fabio Lena, Isabella Zanella, Genni Spargi, Francesco Paciosi, Pier Giorgio Scotton, Simona Dei, Marco Mandalà, Giacomo Zanelli, Alessia Giorli, Elena Bargagli, Maria Palmieri, Stefano Rusconi, Laura Bergantini, Ferdinando Giannattasio, David Bennett, Carmen Marciano, Chiara Spertilli, Maria Bandini, Serena Ludovisi, Enrico Martinelli, Edoardo Conticini, Valentina Anemoli, Nicola Iuso, Elisa Benetti, Matteo Siano, Achille Iolascon, Danilo Tacconi, Mario U. Mondelli, Sara Amitrano, Raffaele Scala, Paolo Piacentini, Lia Crotti, Maria Teresa La Rovere, Nicola Picchiotti, Patrizia Zucchi, Elisabetta Schiaroli, Immacolata Andolfo, Francesca Andretta, Gabriella Doddato, Annarita Giliberti, Stefano Busani, Simona Marcantonio, Antonella d'Arminio Monforte, Mary Ann Belli, Luca Masucci, Rita Perna, Chiara Gabbi, Gabriella Maria Squeo, Franco Maggiolo, Marco Feri, Susanna Guerrini, Paolo Cameli, Elisabetta Menatti, Maurizio Sanguinetti, Andrea Antinori, Lorenzo Salerni, Saverio Giuseppe Parisi, Stefania Mantovani, Floriana Valentino, Federica Gaia Miraglia, Agostino Ognibene, Marco Gori, Renzo Scaggiante, Matteo Della Monica, Giuseppe Merla, Massimo Vaghi, and Massimo Carella

Subjects
Toll-like receptor, Coronavirus disease 2019 (COVID-19), business.industry, Association (object-oriented programming), Nested case-control study, Immunology, Medicine, Disease, business
Published
2021
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43. A pilot study of next generation sequencing–liquid biopsy on cell-free DNA as a novel non-invasive diagnostic tool for Klippel–Trenaunay syndrome

Author

Luca Primo, Aurora Currò, Margherita Baldassarri, Gabriella Doddato, Francesco Molinaro, Benedetta Mussolin, Elisa Frullanti, Maria Palmieri, Massimo Vaghi, Alessandra Renieri, Annarita Giliberti, Chiara Fallerini, Laura di Blasio, Valentina Monica, Laura Di Sarno, and Anna Maria Pinto

Subjects
Male, Klippel-Trenaunay-Weber Syndrome, Pathology, Klippel-Trenaunay syndrome, cell-free DNA-next generation sequencing–liquid biopsy, Klippel–Trenaunay syndrome, non-invasive technique, PIK3CA mutation, Slow-flow vascular malformations, vascular system injuries, Somatic cell, Pilot Projects, 030204 cardiovascular system & hematology, 0302 clinical medicine, Medicine, 0303 health sciences, Mosaicism, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Prognosis, Phenotype, Cell-free fetal DNA, Female, Cardiology and Cardiovascular Medicine, Cell-Free Nucleic Acids, Adult, Genetic Markers, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Clinical Decision-Making, DNA sequencing, 03 medical and health sciences, PIK3CA gene, Predictive Value of Tests, Humans, Radiology, Nuclear Medicine and imaging, Liquid biopsy, 030304 developmental biology, business.industry, Pik3ca mutation, Non invasive, Liquid Biopsy, DNA, Sequence Analysis, DNA, medicine.disease, Mutation, Surgery, business
Abstract

Objectives Somatic mosaicism of PIK3CA gene is currently recognized as the molecular driver of Klippel–Trenaunay syndrome. However, given the limitation of the current technologies, PIK3CA somatic mutations are detected only in a limited proportion of Klippel–Trenaunay syndrome cases and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next generation sequencing liquid biopsy using cell-free DNA has emerged as an innovative non-invasive approach for early detection and monitoring of cancer. This approach, overcoming the space-time profile constraint of tissue biopsies, opens a new scenario also for others diseases caused by somatic mutations. Methods In the present study, we performed a comprehensive analysis of seven patients (four females and three males) with Klippel–Trenaunay syndrome. Blood samples from both peripheral and efferent vein from malformation were collected and cell-free DNA was extracted from plasma. Tissue biopsies from vascular lesions were also collected when available. Cell-free DNA libraries were performed using Oncomine™ Pan-Cancer Cell-Free Assay. Ion Proton for sequencing and Ion Reporter Software for analysis were used (Life Technologies, Carlsbad, CA, USA). Results Cell-free circulating DNA analysis revealed pathogenic mutations in PIK3CA gene in all patients. The mutational load was higher in plasma obtained from the efferent vein at lesional site (0.81%) than in the peripheral vein (0.64%) leading to conclude for a causative role of the identified variants. Tissue analysis, available for one amputated patient, confirmed the presence of the mutation at the malformation site at a high molecular frequency (14–25%), confirming its causative role. Conclusions Our data prove for the first time that the cell-free DNA-next generation sequencing–liquid biopsy, which is currently used exclusively in an oncologic setting, is indeed the most effective tool for Klippel–Trenaunay syndrome diagnosis and tailored personalized treatment.

Published
2021

44. Ixekizumab improves disease severity, clinical symptoms and quality of life in patients with genital psoriasis: A 24-week real-life experience

Author

Gianluca Calianno, Maria Palmieri, Maria Concetta Fargnoli, Maria Esposito, and Rosaria Fidanza

Subjects
Adult, medicine.medical_specialty, Ixekizumab, Dermatology, Disease, Antibodies, Monoclonal, Humanized, Severity of Illness Index, Antibodies, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Psoriasis Area and Severity Index, Internal medicine, Psoriasis, anti-IL17, Monoclonal, medicine, Humans, Sex organ, Genitalia, Adverse effect, Humanized, business.industry, General Medicine, psoriasis, medicine.disease, Clinical trial, genital, quality of life, Quality of Life, Treatment Outcome, Dermatologic Agents, 030220 oncology & carcinogenesis, business
Abstract

Genital psoriasis (GenPs) has been traditionally considered a difficult to treat psoriasis area. Ixekizumab was the first biologic agent demonstrating efficacy and safety in a formal clinical trial on GenPs; however, real-life experiences are limited. To assess real-life effectiveness and safety of ixekizumab in the treatment of GenPs in a case series of patients with moderate-to-severe plaque psoriasis. Adult patients with moderate-to-severe plaque psoriasis involving the genital area received subcutaneous ixekizumab. Evaluation of disease severity, clinical symptoms, and quality of life was performed at baseline, after 4, 16, and 24 weeks of treatment. Assessment tools were: Static Physician's Global Assessment of Genitalia (sPGA-G), Psoriasis Area and Severity Index (PASI) score, Itch Numerical-Rating-Score (Itch-NRS), and Dermatology-Life-Quality-Index (DLQI). Adverse events were recorded. A total of 14 patients were treated with ixekizumab achieving consistent and significant reduction of disease and quality of life parameters, with a mean percentage reduction from baseline to week 24 of 91.4% for sPGA-G, 95.2% for PASI, 95.6% for Itch-NRS, and 93.7% for DLQI. Ixekizumab treatment was well tolerated. Ixekizumab significantly improved disease severity, itch, and quality of life with an acceptable safety profile in a real-life setting in adult patients affected by GenPs.

Published
2021

45. Private somatic mutations identified with liquid biopsy lead tumor progression in solid cancers

Author

Francesco Cetta, Maria Antonietta Mencarelli, Margherita Baldassarri, Nicola Iuso, Alessandra Fabbiani, Rossella Tita, Elisa Frullanti, Alessandra Renieri, Maria Palmieri, Francesca Fava, and Chiara Fallerini

Subjects
Oncology, Cell-free fetal DNA, business.industry, Tumor progression, Somatic cell, Cancer research, Medicine, Liquid biopsy, business, Lead (electronics)
Published
2020
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48. Noninvasive Genetic Testing: Adhesive Patch-Based Skin Biopsy and Buccal Swab

Author

Alessandra Renieri, Maria Palmieri, and Elisa Frullanti

Subjects
medicine.medical_specialty, stomatognathic system, medicine.diagnostic_test, business.industry, Buccal swab, Skin biopsy, Medicine, business, Dermatology field, Dermatology, Genetic testing, Tissue biopsy
Abstract

Driven by the compelling need for noninvasive approach for skin biopsy, adhesive patch-based strategies as well as buccal swab were developed for genetic testing in dermatology field. In this chapter, we will describe the adopted strategies discussing possible advantages and disadvantages.

Published
2020
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50. Safety and efficacy of certolizumab pegol in a real-life cohort of patients with psoriasis and psoriatic arthritis

Author

Alessandra Ventura, Roberto Giacomelli, Sara Tambone, Paola Cipriani, Rosaria Fidanza, Maria Concetta Fargnoli, Maria Palmieri, and Francesco Carubbi

Subjects
Adult, Male, medicine.medical_specialty, Dermatology, Injections, Cohort Studies, 030207 dermatology & venereal diseases, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Psoriasis, Humans, Medicine, Patient Reported Outcome Measures, Certolizumab pegol, certolizumab pegol, dermatology/rheumatology combined outpatient clinic, psoriatic arthritis, 030203 arthritis & rheumatology, Tumor Necrosis Factor-alpha, business.industry, Arthritis, Psoriatic, Middle Aged, medicine.disease, humanities, Methotrexate, Treatment Outcome, Cohort, Quality of Life, Drug Therapy, Combination, Female, Observational study, business, Immunosuppressive Agents, medicine.drug
Abstract

Background: The aim of this observational study was to assess safety and efficacy of certolizumab pegol (CZP) in a real-life cohort of patients affected by psoriasis (PsO) and psoriatic arthritis (...

Published
2020

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