32 results on '"Contino S"'
Search Results
2. 1582P Pregnancy and miscarriage in epithelial ovarian cancer (EOC) patients harboring mutational signature of homologous recombination deficiency (HRD)
- Author
-
Incorvaia, L., Bazan Russo, T.D., Perez, A., Brando, C., Ferraro, P., Simone, A., Bono, M., Castellana, L., Insalaco, L., Contino, S., Gottardo, A., Gristina, V., Galvano, A., Corsini, L.R., Fanale, D., Badalamenti, G., Russo, A., and Bazan, V.
- Published
- 2024
- Full Text
- View/download PDF
3. P-264 The molecular-metabolic interplay in metastatic gastrointestinal stromal tumors (GISTs): The predictive role of body mass index
- Author
-
Incorvaia, L., primary, Brando, C., additional, Algeri, L., additional, Dimino, A., additional, Pedone, E., additional, Schiacchitano, R., additional, Magrin, L., additional, Fiorino, A., additional, Perez, A., additional, Barraco, N., additional, Bono, M., additional, Cancelliere, D., additional, Pivetti, A., additional, Bazan Russo, T., additional, Contino, S., additional, Gristina, V., additional, Galvano, A., additional, Bazan, V., additional, Russo, A., additional, and Badalamenti, G., additional
- Published
- 2022
- Full Text
- View/download PDF
4. Interpretation of intraoperative parathyroid hormone monitoring according to the Rome criterion in primary hyperparathyroidism
- Author
-
Giuseppa Graceffa, Calogero Cipolla, Silvia Calagna, Silvia Contino, Giuseppina Melfa, Giuseppina Orlando, Riccardo Antonini, Alessandro Corigliano, Maria Pia Proclamà, Sergio Mazzola, Gianfranco Cocorullo, Gregorio Scerrino, Graceffa G., Cipolla C., Calagna S., Contino S., Melfa G., Orlando G., Antonini R., Corigliano A., Proclama M.P., Mazzola S., Cocorullo G., and Scerrino G.
- Subjects
Adenoma ,Parathyroidectomy ,Parathyroid Neoplasms ,Multidisciplinary ,Parathyroid Hormone ,Rome ,Humans ,Reproducibility of Results ,intraoperative parathyroid hormone monitoring ,primary hyperparathyroidism ,Hyperparathyroidism, Primary ,Retrospective Studies - Abstract
Intraoperative parathyroid hormone dosage allows real-time monitoring of the decrease in PTH levels during parathyroidectomy and verify procedure’s efficacy. Currently, none of the interpretative criteria used has absolute accuracy. The aim of this study is to evaluate diagnostic accuracy of the Rome criterion verifying diagnostic significance of the individual assays. A total of 205 patients with primary hyperparathyroidism from a single adenoma were retrospectively evaluated and monitored with baseline PTH, PTH at 10 min and PTH at 20 min after adenoma excision. The accuracy of the latter two assays compared with baseline was compared by ROC curves. In addition, was evaluated the influence on these data of localization diagnostics (ultrasounds and scintigraphy), definitive histology, and type of surgery performed. The ratio of 20-min sampling to baseline in the Rome criterion showed highest diagnostic significance. This finding was not influenced by the type of surgery performed, definitive histologic examination, or intraoperative localization of the adenoma. The Rome criterion has shown its high reliability in detecting persistence. The ratio of sampling at 20 min to baseline is by far the best performing. Further studies are needed to evaluate whether sampling at 10 min after adenoma excision can be considered not mandatory.
- Published
- 2022
5. EMBER—Embedding Multiple Molecular Fingerprints for Virtual Screening
- Author
-
Ugo Perricone, Isabella Mendolia, Salvatore Contino, Giada De Simone, Roberto Pirrone, Mendolia I., Contino S., De Simone G., Perricone U., and Pirrone R.
- Subjects
Settore ING-INF/05 - Sistemi Di Elaborazione Delle Informazioni ,Binding Sites ,Molecular Structure ,Deep learning, Drug design, Embedding, Virtual screening ,Research ,Organic Chemistry ,General Medicine ,Ligands ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,CDC2 Protein Kinase ,Drug Discovery ,Mass Screening ,deep learning ,drug design ,virtual screening ,embedding ,Neural Networks, Computer ,Physical and Theoretical Chemistry ,Protein Kinases ,Molecular Biology ,Spectroscopy - Abstract
In recent years, the debate in the field of applications of Deep Learning to Virtual Screening has focused on the use of neural embeddings with respect to classical descriptors in order to encode both structural and physical properties of ligands and/or targets. The attention on embeddings with the increasing use of Graph Neural Networks aimed at overcoming molecular fingerprints that are short range embeddings for atomic neighborhoods. Here, we present EMBER, a novel molecular embedding made by seven molecular fingerprints arranged as different “spectra” to describe the same molecule, and we prove its effectiveness by using deep convolutional architecture that assesses ligands’ bioactivity on a data set containing twenty protein kinases with similar binding sites to CDK1. The data set itself is presented, and the architecture is explained in detail along with its training procedure. We report experimental results and an explainability analysis to assess the contribution of each fingerprint to different targets.
- Published
- 2022
6. Value of Neurostimulation Plus Laryngeal Palpation to Predict Postoperative Vocal Fold Motility
- Author
-
Giuseppa Graceffa, Salvatore Vieni, Silvia Contino, Mario Adelfio Latteri, Calogero Cipolla, Pietro Genova, Cipolla C., Vieni S., Genova P., Contino S., Latteri M., and Graceffa G.
- Subjects
medicine.medical_specialty ,Nerve injury ,medicine.medical_treatment ,Laryngoscopy ,Intraoperative nerve monitoring ,Vocal Cords ,Palpation ,Thyroid carcinoma ,medicine ,Recurrent laryngeal nerve ,Humans ,Neurostimulation ,Retrospective Studies ,Laryngeal palpation ,medicine.diagnostic_test ,business.industry ,Recurrent Laryngeal Nerve ,Thyroid disease ,Thyroidectomy ,Reproducibility of Results ,medicine.disease ,Surgery ,Recurrent Laryngeal Nerve Injuries ,False positive rate ,business ,Vocal Cord Paralysis - Abstract
Background The aim of this study was to evaluate the reliability of intraoperative neuromonitoring through recurrent laryngeal nerve stimulation and simultaneous laryngeal palpation (NSLP) in predicting postoperative vocal cord palsy and in providing useful information in the decision to perform a staged surgery in initially planned total thyroidectomy. Materials and Methods A retrospective review was performed involving 552 patients for whom a total thyroidectomy was planned. In all patients, preoperative and postoperative laryngoscopy was performed. The incidence of vocal cord palsy was calculated on 1104 nerves at risk. Results Sensitivity and specificity of NSLP were 0.9411 and 0.9925 respectively. The positive predictive value was 0.7804, the negative predictive value was 0.9981, the false positive rate was 0.8%. In 41 patients (7.4%) the initial surgical strategy was changed into a staged procedure. Nine patients (21.9%) were false positive, 32 patients (78.1%) were true positive. Finally, a two-stage thyroidectomy was performed in 27 of 41 patients. Conclusions High sensitivity and specificity confirm the validity of NSLP in predicting postoperative vocal cord palsy and in driving a possible staged thyroidectomy, both in benign thyroid disease and in differentiated thyroid carcinoma.
- Published
- 2021
7. Convolutional architectures for virtual screening
- Author
-
Isabella Mendolia, Salvatore Contino, Roberto Pirrone, Ugo Perricone, Edoardo Ardizzone, Mendolia I., Contino S., Perricone U., Ardizzone E., and Pirrone R.
- Subjects
Virtual screening ,Computer science ,lcsh:Computer applications to medicine. Medical informatics ,Machine learning ,computer.software_genre ,01 natural sciences ,Biochemistry ,Drug design ,03 medical and health sciences ,User-Computer Interface ,Structural Biology ,0103 physical sciences ,Representation (mathematics) ,lcsh:QH301-705.5 ,Molecular Biology ,Bioactivity prediction ,Selection (genetic algorithm) ,030304 developmental biology ,Settore ING-INF/05 - Sistemi Di Elaborazione Delle Informazioni ,0303 health sciences ,010304 chemical physics ,business.industry ,Applied Mathematics ,Research ,Process (computing) ,Deep learning ,Computer Science Applications ,lcsh:Biology (General) ,Molecular fingerprints ,lcsh:R858-859.7 ,Artificial intelligence ,DNA microarray ,business ,computer ,Algorithms - Abstract
Background A Virtual Screening algorithm has to adapt to the different stages of this process. Early screening needs to ensure that all bioactive compounds are ranked in the first positions despite of the number of false positives, while a second screening round is aimed at increasing the prediction accuracy. Results A novel CNN architecture is presented to this aim, which predicts bioactivity of candidate compounds on CDK1 using a combination of molecular fingerprints as their vector representation, and has been trained suitably to achieve good results as regards both enrichment factor and accuracy in different screening modes (98.55% accuracy in active-only selection, and 98.88% in high precision discrimination). Conclusion The proposed architecture outperforms state-of-the-art ML approaches, and some interesting insights on molecular fingerprints are devised.
- Published
- 2020
8. A convolutional neural network for virtual screening of molecular fingerprints
- Author
-
Ugo Perricone, Isabella Mendolia, Salvatore Contino, Roberto Pirrone, Edoardo Ardizzone, Elisa Ricci, Samuel Rota Bulò, Cees Snoek, Oswald Lanz, Stefano Messelodi, Nicu Sebe, Mendolia I., Contino S., Perricone U., Pirrone R., and Ardizzone E.
- Subjects
Structure (mathematical logic) ,0303 health sciences ,Virtual screening ,010304 chemical physics ,Point (typography) ,Computer science ,business.industry ,Deep learning ,Process (computing) ,Pattern recognition ,01 natural sciences ,Convolutional neural network ,Drug design ,Set (abstract data type) ,03 medical and health sciences ,Deep Learning ,Virtual Screening ,0103 physical sciences ,Molecular fingerprints ,Embedding ,Artificial intelligence ,business ,Bioactivity prediction ,030304 developmental biology - Abstract
In the last few years, Deep Learning (DL) gained more and more impact on drug design because it allows a huge increase of the prediction accuracy in many stages of such a complex process. In this paper a Virtual Screening (VS) procedure based on Convolutional Neural Networks (CNN) is presented, that is aimed at classifying a set of candidate compounds as regards their biological activity on a particular target protein. The model has been trained on a dataset of active/inactive compounds with respect to the Cyclin-Dependent Kinase 1 (CDK1) a very important protein family, which is heavily involved in regulating the cell cycle. One qualifying point of the proposed approach is the use of molecular fingerprints as a suitable embedding for describing molecules; upto our knowledge there is no Deep Learning approach for VS that makes use of such descriptor. Several kinds of fingerprints are reported in the scientific literature to address different aspects of both the structure and the local properties of a molecule. Both 1D and 2D CNNs have been trained to test the performance of each single descriptor separately, along with suitable ensembles of multiple descriptors for the same compound; the best performing architecture has been used for prediction. The CNN architectures are described in detail, and the results are compared with some recent approaches for Virtual Screening with respect to Cyclin-Dependent Kinase proteins that do not use molecular fingerprints as their descriptor.
- Published
- 2019
9. The intersection of homologous recombination (HR) and mismatch repair (MMR) pathways in DNA repair-defective tumors.
- Author
-
Incorvaia L, Bazan Russo TD, Gristina V, Perez A, Brando C, Mujacic C, Di Giovanni E, Bono M, Contino S, Ferrante Bannera C, Vitale MC, Gottardo A, Peri M, Galvano A, Fanale D, Badalamenti G, Russo A, and Bazan V
- Abstract
Homologous recombination (HR) and mismatch repair (MMR) defects are driver mutational imprints and actionable biomarkers in DNA repair-defective tumors. Although usually thought as mutually exclusive pathways, recent preclinical and clinical research provide preliminary evidence of a functional crosslink and crosstalk between HRR and MMR. Shared core proteins are identified as key players in both pathways, broadening the concept of DNA repair mechanism exclusivity in specific tumor types. These observations may result in unexplored forms of synthetic lethality or hypermutable tumor phenotypes, potentially impacting the cancer risk management, and considerably expanding in the future the therapeutic window for DNA repair-defective tumors., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
10. Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.
- Author
-
Bazan Russo TD, Mujacic C, Di Giovanni E, Vitale MC, Ferrante Bannera C, Randazzo U, Contino S, Bono M, Gristina V, Galvano A, Perez A, Badalamenti G, Russo A, Bazan V, and Incorvaia L
- Abstract
The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
11. Exploring the potential of multiomics liquid biopsy testing in the clinical setting of lung cancer.
- Author
-
Gottardo A, Russo TDB, Perez A, Bono M, Di Giovanni E, Di Marco E, Siino R, Bannera CF, Mujacic C, Vitale MC, Contino S, Iannì G, Busuito G, Iacono F, Incorvaia L, Badalamenti G, Galvano A, Russo A, Bazan V, and Gristina V
- Subjects
- Humans, Liquid Biopsy methods, Artificial Intelligence, Multiomics, Lung Neoplasms pathology, Lung Neoplasms diagnosis, Biomarkers, Tumor
- Abstract
The transformative role of artificial intelligence (AI) and multiomics could enhance the diagnostic and prognostic capabilities of liquid biopsy (LB) for lung cancer (LC). Despite advances, the transition from tissue biopsies to more sophisticated, non-invasive methods like LB has been impeded by challenges such as the heterogeneity of biomarkers and the low concentration of tumour-related analytes. The advent of multiomics - enabled by deep learning algorithms - offers a solution by allowing the simultaneous analysis of various analytes across multiple biological fluids, presenting a paradigm shift in cancer diagnostics. Through multi-marker, multi-analyte and multi-source approaches, this review showcases how AI and multiomics are identifying clinically valuable biomarker combinations that correlate with patients' health statuses. However, the path towards clinical implementation is fraught with challenges, including study reproducibility and lack of methodological standardization, thus necessitating urgent solutions to solve these common issues., (© 2024 John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
12. IODeep: An IOD for the introduction of deep learning in the DICOM standard.
- Author
-
Contino S, Cruciata L, Gambino O, and Pirrone R
- Subjects
- Artificial Intelligence, Computers, Software, Radiology Information Systems, Deep Learning
- Abstract
Background and Objective: In recent years, Artificial Intelligence (AI) and in particular Deep Neural Networks (DNN) became a relevant research topic in biomedical image segmentation due to the availability of more and more data sets along with the establishment of well known competitions. Despite the popularity of DNN based segmentation on the research side, these techniques are almost unused in the daily clinical practice even if they could support effectively the physician during the diagnostic process. Apart from the issues related to the explainability of the predictions of a neural model, such systems are not integrated in the diagnostic workflow, and a standardization of their use is needed to achieve this goal., Methods: This paper presents IODeep a new DICOM Information Object Definition (IOD) aimed at storing both the weights and the architecture of a DNN already trained on a particular image dataset that is labeled as regards the acquisition modality, the anatomical region, and the disease under investigation., Results: The IOD architecture is presented along with a DNN selection algorithm from the PACS server based on the labels outlined above, and a simple PACS viewer purposely designed for demonstrating the effectiveness of the DICOM integration, while no modifications are required on the PACS server side. Also a service based architecture in support of the entire workflow has been implemented., Conclusion: IODeep ensures full integration of a trained AI model in a DICOM infrastructure, and it is also enables a scenario where a trained model can be either fine-tuned with hospital data or trained in a federated learning scheme shared by different hospitals. In this way AI models can be tailored to the real data produced by a Radiology ward thus improving the physician decision making process. Source code is freely available at https://github.com/CHILab1/IODeep.git., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
13. Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints.
- Author
-
Fanale D, Corsini LR, Bono M, Randazzo U, Barraco N, Brando C, Cancelliere D, Contino S, Giurintano A, Magrin L, Pedone E, Perez A, Piraino P, Pivetti A, Giovanni ED, Russo TDB, Prestifilippo O, Gennusa V, Pantuso G, Russo A, and Bazan V
- Subjects
- Humans, Female, Clinical Relevance, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Tumor Microenvironment genetics, MicroRNAs genetics, Exosomes genetics, Exosomes metabolism, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms therapy, Extracellular Vesicles metabolism, Extracellular Vesicles pathology
- Abstract
Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
- Full Text
- View/download PDF
14. Correction: Curation of causal interactions mediated by genes associated with autism accelerates the understanding of gene-phenotype relationships underlying neurodevelopmental disorders.
- Author
-
Iannuccelli M, Vitriolo A, Licata L, Lo Surdo P, Contino S, Cheroni C, Capocefalo D, Castagnoli L, Testa G, Cesareni G, and Perfetto L
- Published
- 2024
- Full Text
- View/download PDF
15. Curation of causal interactions mediated by genes associated with autism accelerates the understanding of gene-phenotype relationships underlying neurodevelopmental disorders.
- Author
-
Iannuccelli M, Vitriolo A, Licata L, Lo Surdo P, Contino S, Cheroni C, Capocefalo D, Castagnoli L, Testa G, Cesareni G, and Perfetto L
- Subjects
- Humans, Gene Regulatory Networks genetics, Autistic Disorder genetics, Genetic Association Studies methods, Proteome genetics, Phenotype, Autism Spectrum Disorder genetics, Genetic Predisposition to Disease genetics, Neurodevelopmental Disorders genetics
- Abstract
Autism spectrum disorder (ASD) comprises a large group of neurodevelopmental conditions featuring, over a wide range of severity and combinations, a core set of manifestations (restricted sociality, stereotyped behavior and language impairment) alongside various comorbidities. Common and rare variants in several hundreds of genes and regulatory regions have been implicated in the molecular pathogenesis of ASD along a range of causation evidence strength. Despite significant progress in elucidating the impact of few paradigmatic individual loci, such sheer complexity in the genetic architecture underlying ASD as a whole has hampered the identification of convergent actionable hubs hypothesized to relay between the vastness of risk alleles and the core phenotypes. In turn this has limited the development of strategies that can revert or ameliorate this condition, calling for a systems-level approach to probe the cross-talk of cooperating genes in terms of causal interaction networks in order to make convergences experimentally tractable and reveal their clinical actionability. As a first step in this direction, we have captured from the scientific literature information on the causal links between the genes whose variants have been associated with ASD and the whole human proteome. This information has been annotated in a computer readable format in the SIGNOR database and is made freely available in the resource website. To link this information to cell functions and phenotypes, we have developed graph algorithms that estimate the functional distance of any protein in the SIGNOR causal interactome to phenotypes and pathways. The main novelty of our approach resides in the possibility to explore the mechanistic links connecting the suggested gene-phenotype relations., (© 2023. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
16. Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?
- Author
-
Incorvaia L, Perez A, Marchetti C, Brando C, Gristina V, Cancelliere D, Pivetti A, Contino S, Di Giovanni E, Barraco N, Bono M, Giurintano A, Bazan Russo TD, Gottardo A, Cutaia S, Pedone E, Peri M, Corsini LR, Fanale D, Galvano A, Scambia G, Badalamenti G, Russo A, and Bazan V
- Subjects
- Humans, Female, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Precision Medicine, Homologous Recombination, BRCA2 Protein genetics, BRCA1 Protein genetics, Biomarkers, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Ovarian Neoplasms drug therapy
- Abstract
Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
17. Potential agnostic role of BRCA alterations in patients with several solid tumors: One for all, all for one?
- Author
-
Fanale D, Corsini LR, Pedone E, Randazzo U, Fiorino A, Di Piazza M, Brando C, Magrin L, Contino S, Piraino P, Bazan Russo TD, Cipolla C, Russo A, and Bazan V
- Subjects
- Female, Humans, BRCA2 Protein genetics, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, BRCA1 Protein genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Germline BRCA1/2 alterations in the Homologous Recombination (HR) pathway are considered as main susceptibility biomarkers to Hereditary Breast and Ovarian Cancers (HBOC). The modern molecular biology technologies allowed to characterize germline and somatic BRCA1/2 alterations in several malignancies, broadening the landscape of BRCA1/2-alterated tumors. In the last years, BRCA genetic testing, beyond the preventive value, also assumed a predictive and prognostic significance for patient management. The approval of molecules with agnostic indication is leading to a new clinical model, defined "mutational". Among these drugs, the Poly (ADP)-Ribose Polymerase inhibitors (PARPi) for BRCA1/2-deficient tumors were widely studied leading to increasing therapeutic implications. In this Review we provided an overview of the main clinical studies describing the association between BRCA-mutated tumors and PARPi response, focusing on the controversial evidence about the potential agnostic indication based on BRCA1/2 alterations in several solid tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
18. SIGNOR 3.0, the SIGnaling network open resource 3.0: 2022 update.
- Author
-
Lo Surdo P, Iannuccelli M, Contino S, Castagnoli L, Licata L, Cesareni G, and Perfetto L
- Subjects
- Humans, COVID-19, Phosphorylation, SARS-CoV-2 genetics, Signal Transduction, Gene Expression Regulation, Databases, Protein
- Abstract
The SIGnaling Network Open Resource (SIGNOR 3.0, https://signor.uniroma2.it) is a public repository that captures causal information and represents it according to an 'activity-flow' model. SIGNOR provides freely-accessible static maps of causal interactions that can be tailored, pruned and refined to build dynamic and predictive models. Each signaling relationship is annotated with an effect (up/down-regulation) and with the mechanism (e.g. binding, phosphorylation, transcriptional activation, etc.) causing the regulation of the target entity. Since its latest release, SIGNOR has undergone a significant upgrade including: (i) a new website that offers an improved user experience and novel advanced search and graph tools; (ii) a significant content growth adding up to a total of approx. 33,000 manually-annotated causal relationships between more than 8900 biological entities; (iii) an increase in the number of manually annotated pathways, currently including pathways deregulated by SARS-CoV-2 infection or involved in neurodevelopment synaptic transmission and metabolism, among others; (iv) additional features such as new model to represent metabolic reactions and a new confidence score assigned to each interaction., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
- Full Text
- View/download PDF
19. Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors.
- Author
-
Dimino A, Brando C, Algeri L, Gristina V, Pedone E, Peri M, Perez A, De Luca I, Sciacchitano R, Magrin L, Bazan Russo TD, Bono M, Barraco N, Contino S, La Mantia M, Galvano A, Badalamenti G, Russo A, Bazan V, and Incorvaia L
- Abstract
Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST.
- Published
- 2022
- Full Text
- View/download PDF
20. Risk Factors for Anaplastic Thyroid Carcinoma: A Case Series From a Tertiary Referral Center for Thyroid Surgery and Literature Analysis.
- Author
-
Graceffa G, Salamone G, Contino S, Saputo F, Corigliano A, Melfa G, Proclamà MP, Richiusa P, Mazzola S, Tutino R, Orlando G, and Scerrino G
- Abstract
Anaplastic thyroid carcinoma (ATC) is a very rare and extremely aggressive disease with a very poor prognosis. Several risk factors have been hypothesized, but there is no clear-cut literature data on it. We reviewed the literature concerning risk factors for ATC and analyzed the institutional database from 2005 to 2022. In total, 15 papers were suitable for review, while the retrospective data collection search, conducted on our institutional database, provided 13 results. In our experience, in agreement with literature data, ATC seems to be a neoplasm peculiar to old age (in our database, mean age is 72 years), with a higher prevalence in subjects with a low level of education and a long history of multinodular goiter (MNG). The role of cigarette smoking and blood group, hypothesized on some literature data, was more uncertain, although the small sample size evaluated probably had a great influence on these results. The higher incidence of the disease in individuals with a history of MNG could suggest more aggressive choices in the treatment of a benign disease, in contrast to current practice. However, this may be a highly questionable point considering that ATC accounts for no more than 2% of all thyroid neoplasms in surgical departments, even those dedicated to endocrine neck surgery. Further studies are therefore necessary for a step forward in this direction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Graceffa, Salamone, Contino, Saputo, Corigliano, Melfa, Proclamà, Richiusa, Mazzola, Tutino, Orlando and Scerrino.)
- Published
- 2022
- Full Text
- View/download PDF
21. Interpretation of intraoperative parathyroid hormone monitoring according to the Rome criterion in primary hyperparathyroidism.
- Author
-
Graceffa G, Cipolla C, Calagna S, Contino S, Melfa G, Orlando G, Antonini R, Corigliano A, Proclamà MP, Mazzola S, Cocorullo G, and Scerrino G
- Subjects
- Humans, Parathyroid Hormone, Parathyroidectomy, Reproducibility of Results, Retrospective Studies, Rome, Adenoma diagnosis, Adenoma surgery, Hyperparathyroidism, Primary diagnosis, Hyperparathyroidism, Primary surgery, Parathyroid Neoplasms diagnosis, Parathyroid Neoplasms surgery
- Abstract
Intraoperative parathyroid hormone dosage allows real-time monitoring of the decrease in PTH levels during parathyroidectomy and verify procedure's efficacy. Currently, none of the interpretative criteria used has absolute accuracy. The aim of this study is to evaluate diagnostic accuracy of the Rome criterion verifying diagnostic significance of the individual assays. A total of 205 patients with primary hyperparathyroidism from a single adenoma were retrospectively evaluated and monitored with baseline PTH, PTH at 10 min and PTH at 20 min after adenoma excision. The accuracy of the latter two assays compared with baseline was compared by ROC curves. In addition, was evaluated the influence on these data of localization diagnostics (ultrasounds and scintigraphy), definitive histology, and type of surgery performed. The ratio of 20-min sampling to baseline in the Rome criterion showed highest diagnostic significance. This finding was not influenced by the type of surgery performed, definitive histologic examination, or intraoperative localization of the adenoma. The Rome criterion has shown its high reliability in detecting persistence. The ratio of sampling at 20 min to baseline is by far the best performing. Further studies are needed to evaluate whether sampling at 10 min after adenoma excision can be considered not mandatory., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
22. EMBER-Embedding Multiple Molecular Fingerprints for Virtual Screening.
- Author
-
Mendolia I, Contino S, De Simone G, Perricone U, and Pirrone R
- Subjects
- Binding Sites, CDC2 Protein Kinase metabolism, Ligands, Mass Screening methods, Molecular Structure, Neural Networks, Computer, Protein Kinases chemistry, Protein Kinases metabolism, Research, Drug Discovery methods
- Abstract
In recent years, the debate in the field of applications of Deep Learning to Virtual Screening has focused on the use of neural embeddings with respect to classical descriptors in order to encode both structural and physical properties of ligands and/or targets. The attention on embeddings with the increasing use of Graph Neural Networks aimed at overcoming molecular fingerprints that are short range embeddings for atomic neighborhoods. Here, we present EMBER, a novel molecular embedding made by seven molecular fingerprints arranged as different "spectra" to describe the same molecule, and we prove its effectiveness by using deep convolutional architecture that assesses ligands' bioactivity on a data set containing twenty protein kinases with similar binding sites to CDK1. The data set itself is presented, and the architecture is explained in detail along with its training procedure. We report experimental results and an explainability analysis to assess the contribution of each fingerprint to different targets.
- Published
- 2022
- Full Text
- View/download PDF
23. Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies.
- Author
-
Vrancx C, Vadukul DM, Suelves N, Contino S, D'Auria L, Perrin F, van Pesch V, Hanseeuw B, Quinton L, and Kienlen-Campard P
- Subjects
- Alzheimer Disease pathology, Animals, Brain pathology, CHO Cells, Cell Line, Tumor, Cricetulus, Fibroblasts metabolism, Humans, Mice, Mice, Transgenic, Neurons metabolism, Neurons pathology, Plaque, Amyloid pathology, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Plaque, Amyloid metabolism, Presenilins metabolism
- Abstract
The β-amyloid peptide (Aβ) is found as amyloid fibrils in senile plaques, a typical hallmark of Alzheimer's disease (AD). However, intermediate soluble oligomers of Aβ are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant Aβ have shown that hexameric Aβ in particular acts as a critical nucleus for Aβ self-assembly. We recently isolated hexameric Aβ assemblies from a cellular model, and demonstrated their ability to enhance Aβ aggregation in vitro. Here, we report the presence of similar hexameric-like Aβ assemblies across several cellular models, including neuronal-like cell lines. In order to better understand how they are produced in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in their formation. PS1 and PS2 are the catalytic subunits of the γ-secretase complex that generates Aβ. Using CRISPR-Cas9 to knockdown each of the two presenilins in neuronal-like cell lines, we observed a direct link between the PS2-dependent processing pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles. Further, we assessed the contribution of hexameric Aβ to the development of amyloid pathology. We report the early presence of hexameric-like Aβ assemblies in both transgenic mice brains exhibiting human Aβ pathology and in the cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a potential early AD biomarker. Finally, cell-derived hexameric Aβ was found to seed other human Aβ forms, resulting in the aggravation of amyloid deposition in vivo and neuronal toxicity in vitro., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
24. Value of Neurostimulation Plus Laryngeal Palpation to Predict Postoperative Vocal Fold Motility.
- Author
-
Cipolla C, Vieni S, Genova P, Contino S, Latteri M, and Graceffa G
- Subjects
- Humans, Palpation, Recurrent Laryngeal Nerve, Reproducibility of Results, Retrospective Studies, Vocal Cords physiopathology, Recurrent Laryngeal Nerve Injuries diagnosis, Recurrent Laryngeal Nerve Injuries etiology, Thyroidectomy adverse effects, Thyroidectomy methods, Vocal Cord Paralysis diagnosis, Vocal Cord Paralysis etiology, Vocal Cord Paralysis physiopathology
- Abstract
Background: The aim of this study was to evaluate the reliability of intraoperative neuromonitoring through recurrent laryngeal nerve stimulation and simultaneous laryngeal palpation (NSLP) in predicting postoperative vocal cord palsy and in providing useful information in the decision to perform a staged surgery in initially planned total thyroidectomy., Materials and Methods: A retrospective review was performed involving 552 patients for whom a total thyroidectomy was planned. In all patients, preoperative and postoperative laryngoscopy was performed. The incidence of vocal cord palsy was calculated on 1104 nerves at risk., Results: Sensitivity and specificity of NSLP were 0.9411 and 0.9925 respectively. The positive predictive value was 0.7804, the negative predictive value was 0.9981, the false positive rate was 0.8%. In 41 patients (7.4%) the initial surgical strategy was changed into a staged procedure. Nine patients (21.9%) were false positive, 32 patients (78.1%) were true positive. Finally, a two-stage thyroidectomy was performed in 27 of 41 patients., Conclusions: High sensitivity and specificity confirm the validity of NSLP in predicting postoperative vocal cord palsy and in driving a possible staged thyroidectomy, both in benign thyroid disease and in differentiated thyroid carcinoma., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
- Full Text
- View/download PDF
25. Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities.
- Author
-
Liaci C, Camera M, Caslini G, Rando S, Contino S, Romano V, and Merlo GR
- Subjects
- Animals, Humans, Intellectual Disability metabolism, Neurons metabolism, Phenotype, Signal Transduction, Cytoskeleton pathology, Intellectual Disability pathology, Neurogenesis, Neurons pathology, Synapses pathology, Systems Biology
- Abstract
Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1-3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.
- Published
- 2021
- Full Text
- View/download PDF
26. An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β.
- Author
-
Vadukul DM, Vrancx C, Burguet P, Contino S, Suelves N, Serpell LC, Quinton L, and Kienlen-Campard P
- Subjects
- Animals, CHO Cells, Cricetulus, Amyloid beta-Peptides chemistry, Biopolymers chemistry
- Abstract
A key hallmark of Alzheimer's disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.
- Published
- 2021
- Full Text
- View/download PDF
27. Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes.
- Author
-
Contino S, Suelves N, Vrancx C, Vadukul DM, Payen VL, Stanga S, Bertrand L, and Kienlen-Campard P
- Abstract
Presenilin 1 (PS1) and Presenilin 2 (PS2) are predominantly known as the catalytic subunits of the γ-secretase complex that generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer's disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. Notably, PSs were found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between these two organelles by controlling the formation of functional MAMs. We have previously demonstrated in mouse embryonic fibroblasts (MEF) an altered mitochondrial morphology along with reduced mitochondrial respiration and increased glycolysis in PS2-deficient cells (PS2KO). This phenotype was restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized cells, and one bottom-line question is to know whether these observations hold true in central nervous system (CNS) cells. To that end, we carried out primary cultures of PS1 knockdown (KD), PS2KO, and PS1KD/PS2KO (PSdKO) neurons and astrocytes. They were obtained from the same litter by crossing PS2 heterozygous; PS1 floxed (PS2
+/- ; PS1flox/flox ) animals. Genetic downregulation of PS1 was achieved by lentiviral expression of the Cre recombinase in primary cultures. Strikingly, we did not observe any mitochondrial phenotype in PS1KD, PS2KO, or PSdKO primary cultures in basal conditions. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+ /NADH ratio. Likewise, mitochondrial morphology and content was unaltered by PS expression. We further investigated the differences between results we obtained here in primary nerve cells and those previously reported in MEF cell lines by analyzing PS2KO primary fibroblasts. We found no mitochondrial dysfunction in this model, in line with observations in PS2KO primary neurons and astrocytes. Together, our results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes, and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might therefore be the consequence of a cell immortalization process and should be critically reconsidered regarding its relevance to AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Contino, Suelves, Vrancx, Vadukul, Payen, Stanga, Bertrand and Kienlen-Campard.)- Published
- 2021
- Full Text
- View/download PDF
28. Convolutional architectures for virtual screening.
- Author
-
Mendolia I, Contino S, Perricone U, Ardizzone E, and Pirrone R
- Subjects
- Algorithms, User-Computer Interface
- Abstract
Background: A Virtual Screening algorithm has to adapt to the different stages of this process. Early screening needs to ensure that all bioactive compounds are ranked in the first positions despite of the number of false positives, while a second screening round is aimed at increasing the prediction accuracy., Results: A novel CNN architecture is presented to this aim, which predicts bioactivity of candidate compounds on CDK1 using a combination of molecular fingerprints as their vector representation, and has been trained suitably to achieve good results as regards both enrichment factor and accuracy in different screening modes (98.55% accuracy in active-only selection, and 98.88% in high precision discrimination)., Conclusion: The proposed architecture outperforms state-of-the-art ML approaches, and some interesting insights on molecular fingerprints are devised.
- Published
- 2020
- Full Text
- View/download PDF
29. Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release.
- Author
-
Opsomer R, Contino S, Perrin F, Gualdani R, Tasiaux B, Doyen P, Vergouts M, Vrancx C, Doshina A, Pierrot N, Octave JN, Gailly P, Stanga S, and Kienlen-Campard P
- Subjects
- Amyloid beta-Peptides, Animals, Basic Helix-Loop-Helix Transcription Factors, Humans, Mice, Synaptic Transmission, Transcription Factors, gamma-Aminobutyric Acid, Alzheimer Disease genetics, Amyloid beta-Protein Precursor genetics
- Abstract
The amyloid precursor protein (APP) has been extensively studied as the precursor of the β-amyloid (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and on maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of neuronal PAS domain protein 4 (NPAS4) in APP-/- neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The downregulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABA
A receptors α1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABAA receptors activity, but long-term potentiation (LTP) measurement supported an increased GABA component in synaptic transmission of APP-/- mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission., (Copyright © 2020 Opsomer et al.)- Published
- 2020
- Full Text
- View/download PDF
30. Presenilin 2-Dependent Maintenance of Mitochondrial Oxidative Capacity and Morphology.
- Author
-
Contino S, Porporato PE, Bird M, Marinangeli C, Opsomer R, Sonveaux P, Bontemps F, Dewachter I, Octave JN, Bertrand L, Stanga S, and Kienlen-Campard P
- Abstract
Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet the mechanisms underlying the impairment of mitochondrial function in AD remain elusive. Recent evidence suggested a role for Presenilins (PS1 or PS2) in mitochondrial function. Mutations of PSs, the catalytic subunits of the γ-secretase complex, are responsible for the majority of inherited AD cases (FAD). PSs were shown to be present in mitochondria and particularly enriched in mitochondria-associated membranes (MAM), where PS2 is involved in the calcium shuttling between mitochondria and the endoplasmic reticulum (ER). We investigated the precise contribution of PS1 and PS2 to the bioenergetics of the cell and to mitochondrial morphology in cell lines derived from wild type (PS+/+), PS1/2 double knock-out (PSdKO), PS2KO and PS1KO embryos. Our results showed a significant impairment in the respiratory capacity of PSdKO and PS2KO cells with reduction of basal oxygen consumption, oxygen utilization dedicated to ATP production and spare respiratory capacity. In line with these functional defects, we found a decrease in the expression of subunits responsible for mitochondrial oxidative phosphorylation (OXPHOS) associated with an altered morphology of the mitochondrial cristae. This OXPHOS disruption was accompanied by a reduction of the NAD
+ /NADH ratio. Still, neither ADP/ATP ratio nor mitochondrial membrane potential (ΔΨ) were affected, suggesting the existence of a compensatory mechanism for energetic balance. We observed indeed an increase in glycolytic flux in PSdKO and PS2KO cells. All these effects were truly dependent on PS2 since its stable re-expression in a PS2KO background led to a complete restoration of the parameters impaired in the absence of PS2. Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics, pointing toward its peculiar role in the formation and integrity of the electron transport chain.- Published
- 2017
- Full Text
- View/download PDF
31. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.
- Author
-
Stanga S, Zanou N, Audouard E, Tasiaux B, Contino S, Vandermeulen G, René F, Loeffler JP, Clotman F, Gailly P, Dewachter I, Octave JN, and Kienlen-Campard P
- Subjects
- Animals, Cells, Cultured, Glial Cell Line-Derived Neurotrophic Factor genetics, Mice, Mice, Knockout, Muscle, Skeletal physiology, Amyloid beta-Protein Precursor metabolism, Fibroblasts physiology, Gene Expression Regulation physiology, Glial Cell Line-Derived Neurotrophic Factor metabolism, Neuromuscular Junction physiology
- Abstract
Besides its crucial role in the pathogenesis of Alzheimer's disease, the knowledge of amyloid precursor protein (APP) physiologic functions remains surprisingly scarce. Here, we show that APP regulates the transcription of the glial cell line-derived neurotrophic factor (GDNF). APP-dependent regulation of GDNF expression affects muscle strength, muscular trophy, and both neuronal and muscular differentiation fundamental for neuromuscular junction (NMJ) maturation in vivo In a nerve-muscle coculture model set up to modelize NMJ formation in vitro, silencing of muscular APP induces a 30% decrease in secreted GDNF levels and a 40% decrease in the total number of NMJs together with a significant reduction in the density of acetylcholine vesicles at the presynaptic site and in neuronal maturation. These defects are rescued by GDNF expression in muscle cells in the conditions where muscular APP has been previously silenced. Expression of GDNF in muscles of amyloid precursor protein null mice corrected the aberrant synaptic morphology of NMJs. Our findings highlight for the first time that APP-dependent GDNF expression drives the process of NMJ formation, providing new insights into the link between APP gene regulatory network and physiologic functions.-Stanga, S., Zanou, N., Audouard, E., Tasiaux, B., Contino, S., Vandermeulen, G., René, F., Loeffler, J.-P., Clotman, F., Gailly, P., Dewachter, I., Octave, J.-N., Kienlen-Campard, P. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation., (© FASEB.)
- Published
- 2016
- Full Text
- View/download PDF
32. Custom shading for temporary-coverage restorations.
- Author
-
Cleveland JL Jr, King CJ, and Contino SH
- Subjects
- Color, Polymers, Acrylic Resins therapeutic use, Dental Restoration, Temporary, Esthetics, Dental, Tooth, Artificial
- Published
- 1974
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.