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Journal Articles
2023
11.
Rocca M S; Minervini G; Vinanzi C; Bottacin A; Lia F; Foresta C; Pennuto M; Ferlin A
Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples Journal Article
In: Journal of Clinical Endocrinology and Metabolism, vol. 108, no. 5, pp. 1181-1191, 2023, (Cited by: 7; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85152486041,
title = {Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples},
author = {Maria Santa Rocca and Giovanni Minervini and Cinzia Vinanzi and Alberto Bottacin and Federica Lia and Carlo Foresta and Maria Pennuto and Alberto Ferlin},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85152486041&origin=inward},
doi = {10.1210/clinem/dgac671},
year = {2023},
date = {2023-01-01},
journal = {Journal of Clinical Endocrinology and Metabolism},
volume = {108},
number = {5},
pages = {1181-1191},
publisher = {Endocrine Society},
abstract = {© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.Context: Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. Objective: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. Methods: A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. Results: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. Conclusion: This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.},
note = {Cited by: 7; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.Context: Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. Objective: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. Methods: A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. Results: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. Conclusion: This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.
12.
Camagni G F; Minervini G; Tosatto S C E
Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations Journal Article
In: International Journal of Molecular Sciences, vol. 24, no. 5, 2023, (Cited by: 7; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85149881431,
title = {Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations},
author = {Giorgia F. Camagni and Giovanni Minervini and Silvio C. E. Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85149881431&origin=inward},
doi = {10.3390/ijms24054710},
year = {2023},
date = {2023-01-01},
journal = {International Journal of Molecular Sciences},
volume = {24},
number = {5},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
abstract = {© 2023 by the authors.The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.},
note = {Cited by: 7; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2023 by the authors.The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.
13.
Conte A D; Monzon A M; Clementel D; Camagni G F; Minervini G; Tosatto S C E; Piovesan D
RING-PyMOL: residue interaction networks of structural ensembles and molecular dynamics Journal Article
In: Bioinformatics, vol. 39, no. 5, 2023, (Cited by: 23; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85159553803,
title = {RING-PyMOL: residue interaction networks of structural ensembles and molecular dynamics},
author = {Alessio Del Conte and Alexander Miguel Monzon and Damiano Clementel and Giorgia F. Camagni and Giovanni Minervini and Silvio C. E. Tosatto and Damiano Piovesan},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85159553803&origin=inward},
doi = {10.1093/bioinformatics/btad260},
year = {2023},
date = {2023-01-01},
journal = {Bioinformatics},
volume = {39},
number = {5},
publisher = {Oxford University Press},
abstract = {© The Author(s) 2023. Published by Oxford University Press.RING-PyMOL is a plugin for PyMOL providing a set of analysis tools for structural ensembles and molecular dynamic simulations. RING-PyMOL combines residue interaction networks, as provided by the RING software, with structural clustering to enhance the analysis and visualization of the conformational complexity. It combines precise calculation of non-covalent interactions with the power of PyMOL to manipulate and visualize protein structures. The plugin identifies and highlights correlating contacts and interaction patterns that can explain structural allostery, active sites, and structural heterogeneity connected with molecular function. It is easy to use and extremely fast, processing and rendering hundreds of models and long trajectories in seconds. RING-PyMOL generates a number of interactive plots and output files for use with external tools. The underlying RING software has been improved extensively. It is 10 times faster, can process mmCIF files and it identifies typed interactions also for nucleic acids.},
note = {Cited by: 23; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© The Author(s) 2023. Published by Oxford University Press.RING-PyMOL is a plugin for PyMOL providing a set of analysis tools for structural ensembles and molecular dynamic simulations. RING-PyMOL combines residue interaction networks, as provided by the RING software, with structural clustering to enhance the analysis and visualization of the conformational complexity. It combines precise calculation of non-covalent interactions with the power of PyMOL to manipulate and visualize protein structures. The plugin identifies and highlights correlating contacts and interaction patterns that can explain structural allostery, active sites, and structural heterogeneity connected with molecular function. It is easy to use and extremely fast, processing and rendering hundreds of models and long trajectories in seconds. RING-PyMOL generates a number of interactive plots and output files for use with external tools. The underlying RING software has been improved extensively. It is 10 times faster, can process mmCIF files and it identifies typed interactions also for nucleic acids.
14.
Piol D; Tosatto L; Zuccaro E; Anderson E N; Falconieri A; Polanco M J; Marchioretti C; Lia F; White J; Bregolin E; Minervini G; Parodi S; Salvatella X; Arrigoni G; Ballabio A; Spada A R L; Tosatto S C E; Sambataro F; Medina D L; Pandey U B; Basso M; Pennuto M
Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function Journal Article
In: Science Advances, vol. 9, no. 1, 2023, (Cited by: 11; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85145870213,
title = {Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function},
author = {Diana Piol and Laura Tosatto and Emanuela Zuccaro and Eric N. Anderson and Antonella Falconieri and Maria J. Polanco and Caterina Marchioretti and Federica Lia and Joseph White and Elisa Bregolin and Giovanni Minervini and Sara Parodi and Xavier Salvatella and Giorgio Arrigoni and Andrea Ballabio and Albert R. La Spada and Silvio C. E. Tosatto and Fabio Sambataro and Diego L. Medina and Udai B. Pandey and Manuela Basso and Maria Pennuto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85145870213&origin=inward},
doi = {10.1126/sciadv.ade1694},
year = {2023},
date = {2023-01-01},
journal = {Science Advances},
volume = {9},
number = {1},
publisher = {American Association for the Advancement of Science},
abstract = {Copyright © 2023 The Authors, some rights reserved;Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.},
note = {Cited by: 11; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Copyright © 2023 The Authors, some rights reserved;Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.
2022
15.
Quaglia F; Meszáros B; Salladini E; Hatos A; Pancsa R; Chemes L B; Pajkos M; Lazar T; Peña-Díaz S; Santos J; Ács V; Farahi N; Fichó E; Aspromonte M C; Bassot C; Chasapi A; Davey N E; Davidović R; Dobson L; Elofsson A; Erdos G; Gaudet P; Giglio M; Glavina J; Iserte J; Iglesias V; Kálmán Z; Lambrughi M; Leonardi E; Longhi S; Macedo-Ribeiro S; Maiani E; Marchetti J; Marino-Buslje C; Meszáros A; Monzon A M; Minervini G; Nadendla S; Nilsson J F; Novotný M; Ouzounis C A; Palopoli N; Papaleo E; Pereira P J B; Pozzati G; Promponas V J; Pujols J; Rocha A C S; Salas M; Sawicki L R; Schad E; Shenoy A; Szaniszló T; Tsirigos K D; Veljkovic N; Parisi G; Ventura S; Dosztányi Z; Tompa P; Tosatto S C E; Piovesan D
DisProt in 2022: Improved quality and accessibility of protein intrinsic disorder annotation Journal Article
In: Nucleic Acids Research, vol. 50, no. D1, pp. D480-D487, 2022, (Cited by: 136; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85125157608,
title = {DisProt in 2022: Improved quality and accessibility of protein intrinsic disorder annotation},
author = {Federica Quaglia and Bálint Meszáros and Edoardo Salladini and András Hatos and Rita Pancsa and Lucía B. Chemes and Mátyás Pajkos and Tamas Lazar and Samuel Peña-Díaz and Jaime Santos and Veronika Ács and Nazanin Farahi and Erzsebet Fichó and Maria Cristina Aspromonte and Claudio Bassot and Anastasia Chasapi and Norman E. Davey and Radoslav Davidović and Laszlo Dobson and Arne Elofsson and Gábor Erdos and Pascale Gaudet and Michelle Giglio and Juliana Glavina and Javier Iserte and Valentín Iglesias and Zsófia Kálmán and Matteo Lambrughi and Emanuela Leonardi and Sonia Longhi and Sandra Macedo-Ribeiro and Emiliano Maiani and Julia Marchetti and Cristina Marino-Buslje and Attila Meszáros and Alexander Miguel Monzon and Giovanni Minervini and Suvarna Nadendla and Juliet F. Nilsson and Marian Novotný and Christos A. Ouzounis and Nicolás Palopoli and Elena Papaleo and Pedro Jose Barbosa Pereira and Gabriele Pozzati and Vasilis J. Promponas and Jordi Pujols and Alma Carolina Sanchez Rocha and Martin Salas and Luciana Rodriguez Sawicki and Eva Schad and Aditi Shenoy and Tamás Szaniszló and Konstantinos D. Tsirigos and Nevena Veljkovic and Gustavo Parisi and Salvador Ventura and Zsuzsanna Dosztányi and Peter Tompa and Silvio C. E. Tosatto and Damiano Piovesan},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85125157608&origin=inward},
doi = {10.1093/nar/gkab1082},
year = {2022},
date = {2022-01-01},
journal = {Nucleic Acids Research},
volume = {50},
number = {D1},
pages = {D480-D487},
publisher = {Oxford University Press},
abstract = {© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.},
note = {Cited by: 136; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.
16.
Clementel D; Conte A D; Monzon A M; Camagni G F; Minervini G; Piovesan D; Tosatto S C E
RING 3.0: fast generation of probabilistic residue interaction networks from structural ensembles Journal Article
In: Nucleic Acids Research, vol. 50, no. W1, pp. W651-W656, 2022, (Cited by: 138; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85134391344,
title = {RING 3.0: fast generation of probabilistic residue interaction networks from structural ensembles},
author = {Damiano Clementel and Alessio Del Conte and Alexander Miguel Monzon and Giorgia F Camagni and Giovanni Minervini and Damiano Piovesan and Silvio C. E Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85134391344&origin=inward},
doi = {10.1093/nar/gkac365},
year = {2022},
date = {2022-01-01},
journal = {Nucleic Acids Research},
volume = {50},
number = {W1},
pages = {W651-W656},
publisher = {Oxford University Press},
abstract = {© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Residue interaction networks (RINs) are used to represent residue contacts in protein structures. Thanks to the advances in network theory, RINs have been proved effective as an alternative to coordinate data in the analysis of complex systems. The RING server calculates high quality and reliable non-covalent molecular interactions based on geometrical parameters. Here, we present the new RING 3.0 version extending the previous functionality in several ways. The underlying software library has been re-engineered to improve speed by an order of magnitude. RING now also supports the mmCIF format and provides typed interactions for the entire PDB chemical component dictionary, including nucleic acids. Moreover, RING now employs probabilistic graphs, where multiple conformations (e.g. NMR or molecular dynamics ensembles) are mapped as weighted edges, opening up new ways to analyze structural data. The web interface has been expanded to include a simultaneous view of the RIN alongside a structure viewer, with both synchronized and clickable. Contact evolution across models (or time) is displayed as a heatmap and can help in the discovery of correlating interaction patterns. The web server, together with an extensive help and tutorial, is available from URL: https://ring.biocomputingup.it/.},
note = {Cited by: 138; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Residue interaction networks (RINs) are used to represent residue contacts in protein structures. Thanks to the advances in network theory, RINs have been proved effective as an alternative to coordinate data in the analysis of complex systems. The RING server calculates high quality and reliable non-covalent molecular interactions based on geometrical parameters. Here, we present the new RING 3.0 version extending the previous functionality in several ways. The underlying software library has been re-engineered to improve speed by an order of magnitude. RING now also supports the mmCIF format and provides typed interactions for the entire PDB chemical component dictionary, including nucleic acids. Moreover, RING now employs probabilistic graphs, where multiple conformations (e.g. NMR or molecular dynamics ensembles) are mapped as weighted edges, opening up new ways to analyze structural data. The web interface has been expanded to include a simultaneous view of the RIN alongside a structure viewer, with both synchronized and clickable. Contact evolution across models (or time) is displayed as a heatmap and can help in the discovery of correlating interaction patterns. The web server, together with an extensive help and tutorial, is available from URL: https://ring.biocomputingup.it/.
17.
Leonardi E; Savojardo C; Minervini G
Molecular Effects of Mutations in Human Genetic Diseases Journal Article
In: International Journal of Molecular Sciences, vol. 23, no. 12, 2022, (Cited by: 0; Open Access).
Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85131521999,
title = {Molecular Effects of Mutations in Human Genetic Diseases},
author = {Emanuela Leonardi and Castrense Savojardo and Giovanni Minervini},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85131521999&origin=inward},
doi = {10.3390/ijms23126408},
year = {2022},
date = {2022-01-01},
journal = {International Journal of Molecular Sciences},
volume = {23},
number = {12},
publisher = {MDPI},
note = {Cited by: 0; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
18.
Catoni C; Poggiana C; Facchinetti A; Pigozzo J; Piccin L; Chiarion-Sileni V; Rosato A; Minervini G; Scaini M C
Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach Journal Article
In: Cancers, vol. 14, no. 17, 2022, (Cited by: 5; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85137888553,
title = {Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach},
author = {Cristina Catoni and Cristina Poggiana and Antonella Facchinetti and Jacopo Pigozzo and Luisa Piccin and Vanna Chiarion-Sileni and Antonio Rosato and Giovanni Minervini and Maria Chiara Scaini},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85137888553&origin=inward},
doi = {10.3390/cancers14174153},
year = {2022},
date = {2022-01-01},
journal = {Cancers},
volume = {14},
number = {17},
publisher = {MDPI},
abstract = {© 2022 by the authors.The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.},
note = {Cited by: 5; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 by the authors.The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.
19.
Fusto A; Cassandrini D; Fiorillo C; Codemo V; Astrea G; D’Amico A; Maggi L; Magri F; Pane M; Tasca G; Sabbatini D; Bello L; Battini R; Bernasconi P; Fattori F; Bertini E S; Comi G; Messina S; Mongini T; Moroni I; Panicucci C; Berardinelli A; Donati A; Nigro V; Pini A; Giannotta M; Dosi C; Ricci E; Mercuri E; Minervini G; Tosatto S; Santorelli F; Bruno C; Pegoraro E
Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study Journal Article
In: Acta Neuropathologica Communications, vol. 10, no. 1, 2022, (Cited by: 14; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85128316270,
title = {Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study},
author = {Aurora Fusto and Denise Cassandrini and Chiara Fiorillo and Valentina Codemo and Guja Astrea and Adele D’Amico and Lorenzo Maggi and Francesca Magri and Marika Pane and Giorgio Tasca and Daniele Sabbatini and Luca Bello and Roberta Battini and Pia Bernasconi and Fabiana Fattori and Enrico Silvio Bertini and Giacomo Comi and Sonia Messina and Tiziana Mongini and Isabella Moroni and Chiara Panicucci and Angela Berardinelli and Alice Donati and Vincenzo Nigro and Antonella Pini and Melania Giannotta and Claudia Dosi and Enzo Ricci and Eugenio Mercuri and Giovanni Minervini and Silvio Tosatto and Filippo Santorelli and Claudio Bruno and Elena Pegoraro},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85128316270&origin=inward},
doi = {10.1186/s40478-022-01357-0},
year = {2022},
date = {2022-01-01},
journal = {Acta Neuropathologica Communications},
volume = {10},
number = {1},
publisher = {BioMed Central Ltd},
abstract = {© 2022, The Author(s).Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.},
note = {Cited by: 14; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022, The Author(s).Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.
20.
Falconieri A; Minervini G; Quaglia F; Sartori G; Tosatto S C E
Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening Journal Article
In: Cancers, vol. 14, no. 4, 2022, (Cited by: 1; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85124955220,
title = {Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening},
author = {Antonella Falconieri and Giovanni Minervini and Federica Quaglia and Geppo Sartori and Silvio C. E. Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85124955220&origin=inward},
doi = {10.3390/cancers14041009},
year = {2022},
date = {2022-01-01},
journal = {Cancers},
volume = {14},
number = {4},
publisher = {MDPI},
abstract = {© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.},
note = {Cited by: 1; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.