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Article: CMA mediates resistance in breast cancer models.

Lo Dico, Alessia / Martelli, C / Corsi, F / Porro, D / Ottobrini, L / Bertoli, G

2023 Volume 23, Issue 1, Page(s) 133

Abstract: Background: Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. ... ...

Abstract	Background: Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. Methods: A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. Results: In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. Conclusion: Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
Language	English
Publishing date	2023-07-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2091573-1
ISSN	1475-2867
ISSN	1475-2867
DOI	10.1186/s12935-023-02969-9
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Article ; Online: Characterization of cell cycle, inflammation, and oxidative stress signaling role in non-communicable diseases: Insights into genetic variants, microRNAs and pathways.

D'Antona, Salvatore / Porro, Danilo / Gallivanone, Francesca / Bertoli, Gloria

Computers in biology and medicine

2024 Volume 174, Page(s) 108346

Abstract: Non-Communicable Diseases (NCDs) significantly impact global health, contributing to over 70% of premature deaths, as reported by the World Health Organization (WHO). These diseases have complex and multifactorial origins, involving genetic, epigenetic, ... ...

Abstract	Non-Communicable Diseases (NCDs) significantly impact global health, contributing to over 70% of premature deaths, as reported by the World Health Organization (WHO). These diseases have complex and multifactorial origins, involving genetic, epigenetic, environmental and lifestyle factors. While Genome-Wide Association Study (GWAS) is widely recognized as a valuable tool for identifying variants associated with complex phenotypes; the multifactorial nature of NCDs necessitates a more comprehensive exploration, encompassing not only the genetic but also the epigenetic aspect. For this purpose, we employed a bioinformatics-multiomics approach to examine the genetic and epigenetic characteristics of NCDs (i.e. colorectal cancer, coronary atherosclerosis, squamous cell lung cancer, psoriasis, type 2 diabetes, and multiple sclerosis), aiming to identify novel biomarkers for diagnosis and prognosis. Leveraging GWAS summary statistics, we pinpointed Single Nucleotide Polymorphisms (SNPs) independently associated with each NCD. Subsequently, we identified genes linked to cell cycle, inflammation and oxidative stress mechanisms, revealing shared genes across multiple diseases, suggesting common functional pathways. From an epigenetic perspective, we identified microRNAs (miRNAs) with regulatory functions targeting these genes of interest. Our findings underscore critical genetic pathways implicated in these diseases. In colorectal cancer, the dysregulation of the "Cytokine Signaling in Immune System" pathway, involving LAMA5 and SMAD7, regulated by Hsa-miR-21-5p, Hsa-miR-103a-3p, and Hsa-miR-195-5p, emerged as pivotal. In coronary atherosclerosis, the pathway associated with "binding of TCF/LEF:CTNNB1 to target gene promoters" displayed noteworthy implications, with the MYC factor controlled by Hsa-miR-16-5p as a potential regulatory factor. Squamous cell lung carcinoma analysis revealed significant pathways such as "PTK6 promotes HIF1A stabilization," regulated by Hsa-let-7b-5p. In psoriasis, the "Endosomal/Vacuolar pathway," involving HLA-C and Hsa-miR-148a-3p and Hsa-miR-148b-3p, was identified as crucial. Type 2 Diabetes implicated the "Regulation of TP53 Expression" pathway, controlled by Hsa-miR-106a-5p and Hsa-miR-106b-5p. In conclusion, our study elucidates the genetic framework and molecular mechanisms underlying NCDs, offering crucial insights into potential genetic/epigenetic biomarkers for diagnosis and prognosis. The specificity of pathways and related miRNAs in different pathologies highlights promising candidates for further clinical validation, with the potential to advance personalized treatments and alleviate the global burden of NCDs.
MeSH term(s)	Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Inflammation/genetics ; Polymorphism, Single Nucleotide ; Oxidative Stress/genetics ; Noncommunicable Diseases ; Genome-Wide Association Study ; Signal Transduction/genetics ; Epigenesis, Genetic
Chemical Substances	MicroRNAs
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	127557-4
ISSN	1879-0534 ; 0010-4825
ISSN (online)	1879-0534
ISSN	0010-4825
DOI	10.1016/j.compbiomed.2024.108346
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Article: Diagnostic Circulating miRNAs in Sporadic Amyotrophic Lateral Sclerosis.

Panio, A / Cava, C / D'Antona, S / Bertoli, G / Porro, D

Frontiers in medicine

2022 Volume 9, Page(s) 861960

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the neurodegeneration of motoneurons. About 10% of ALS is hereditary and involves mutation in 25 different genes, while 90% of the cases are sporadic forms of ALS ( ... ...

Abstract	Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the neurodegeneration of motoneurons. About 10% of ALS is hereditary and involves mutation in 25 different genes, while 90% of the cases are sporadic forms of ALS (sALS). The diagnosis of ALS includes the detection of early symptoms and, as disease progresses, muscle twitching and then atrophy spreads from hands to other parts of the body. The disease causes high disability and has a high mortality rate; moreover, the therapeutic approaches for the pathology are not effective. miRNAs are small non-coding RNAs, whose activity has a major impact on the expression levels of coding mRNA. The literature identifies several miRNAs with diagnostic abilities on sALS, but a unique diagnostic profile is not defined. As miRNAs could be secreted, the identification of specific blood miRNAs with diagnostic ability for sALS could be helpful in the identification of the patients. In the view of personalized medicine, we performed a meta-analysis of the literature in order to select specific circulating miRNAs with diagnostic properties and, by bioinformatics approaches, we identified a panel of 10 miRNAs (miR-193b, miR-3911, miR-139-5p, miR-193b-1, miR-338-5p, miR-3911-1, miR-455-3p, miR-4687-5p, miR-4745-5p, and miR-4763-3p) able to classify sALS patients by blood analysis. Among them, the analysis of expression levels of the couple of blood miR-193b/miR-4745-5p could be translated in clinical practice for the diagnosis of sALS.
Language	English
Publishing date	2022-05-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2022.861960
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Article: The biological interplay between air pollutants and miRNAs regulation in cancer.

Giammona, Alessandro / Remedia, Sofia / Porro, Danilo / Lo Dico, Alessia / Bertoli, Gloria

Frontiers in cell and developmental biology

2024 Volume 12, Page(s) 1343385

Abstract: Air pollution, especially fine particulate matter (PM2.5, with an aerodynamic diameter of less than 2.5 μm), represents a risk factor for human health. Many studies, regarding cancer onset and progression, correlated with the short and/or long exposition ...

Abstract	Air pollution, especially fine particulate matter (PM2.5, with an aerodynamic diameter of less than 2.5 μm), represents a risk factor for human health. Many studies, regarding cancer onset and progression, correlated with the short and/or long exposition to PM2.5. This is mainly mediated by the ability of PM2.5 to reach the pulmonary alveoli by penetrating into the blood circulation. This review recapitulates the methodologies used to study PM2.5 in cellular models and the downstream effects on the main molecular pathways implicated in cancer. We report a set of data from the literature, that describe the involvement of miRNAs or long noncoding RNAs on the main biological processes involved in oxidative stress, inflammation, autophagy (PI3K), cell proliferation (NFkB, STAT3), and EMT (Notch, AKT, Wnt/β-catenin) pathways. microRNAs, as well as gene expression profile, responds to air pollution environment modulating some key genes involved in epigenetic modification or in key mediators of the biological processes described below. In this review, we provide some scientific evidences about the thigh correlation between miRNAs dysregulation, PM2.5 exposition, and gene pathways involved in cancer progression.
Language	English
Publishing date	2024-02-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2024.1343385
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Article ; Online: Intralabyrinthine schwannoma: Surgical management and cochlear lumen preservation.

Liaci, Enrico / Bertoli, Giulia / Di Lella, Filippo / Falcioni, Maurizio

American journal of otolaryngology

2023 Volume 45, Issue 2, Page(s) 104158

Abstract: The present video reports the surgical removal of an intralabyrinthine schwannoma. The video contains patient's medical history, preoperative radiological evaluations and detailed description of surgical steps of the procedure, consisting in ... ...

Abstract	The present video reports the surgical removal of an intralabyrinthine schwannoma. The video contains patient's medical history, preoperative radiological evaluations and detailed description of surgical steps of the procedure, consisting in labyrinthectomy, cochleostomy and insertion of a dummy electrode in the preserved cochlear lumen within the context of a subtotal petrosectomy.
MeSH term(s)	Humans ; Cochlea/diagnostic imaging ; Cochlea/surgery ; Ear, Inner ; Neurilemmoma/diagnostic imaging ; Neurilemmoma/surgery ; Neuroma, Acoustic/diagnostic imaging ; Neuroma, Acoustic/surgery ; Otologic Surgical Procedures/methods
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Case Reports ; Journal Article ; Video-Audio Media
ZDB-ID	604541-8
ISSN	1532-818X ; 0196-0709
ISSN (online)	1532-818X
ISSN	0196-0709
DOI	10.1016/j.amjoto.2023.104158
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Article ; Online: Radiogenomics, Breast Cancer Diagnosis and Characterization: Current Status and Future Directions.

Gallivanone, Francesca / Bertoli, Gloria / Porro, Danilo

Methods and protocols

2022 Volume 5, Issue 5

Abstract: Breast cancer (BC) is a heterogeneous disease, affecting millions of women every year. Early diagnosis is crucial to increasing survival. The clinical workup of BC diagnosis involves diagnostic imaging and bioptic characterization. In recent years, ... ...

Abstract	Breast cancer (BC) is a heterogeneous disease, affecting millions of women every year. Early diagnosis is crucial to increasing survival. The clinical workup of BC diagnosis involves diagnostic imaging and bioptic characterization. In recent years, technical advances in image processing allowed for the application of advanced image analysis (radiomics) to clinical data. Furthermore, -omics technologies showed their potential in the characterization of BC. Combining information provided by radiomics with -omics data can be important to personalize diagnostic and therapeutic work up in a clinical context for the benefit of the patient. In this review, we analyzed the recent literature, highlighting innovative approaches to combine imaging and biochemical/biological data, with the aim of identifying recent advances in radiogenomics applied to BC. The results of radiogenomic studies are encouraging approaches in a clinical setting. Despite this, as radiogenomics is an emerging area, the optimal approach has to face technical limitations and needs to be applied to large cohorts including all the expression profiles currently available for BC subtypes (e.g., besides markers from transcriptomics, proteomics and miRNomics, also other non-coding RNA profiles).
Language	English
Publishing date	2022-10-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2409-9279
ISSN (online)	2409-9279
DOI	10.3390/mps5050078
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Article ; Online: Management of complicated temporal bone fracture.

Bertoli, Giulia / Falcioni, Maurizio / Salis, Giada

American journal of otolaryngology

2022 Volume 44, Issue 2, Page(s) 103783

Abstract: The current video presents the surgical management of a complicated temporal bone fracture. The video contains patient's medical history, preoperative radiological evaluations, and detailed surgical approach to manage the disease. The current video ... ...

Abstract	The current video presents the surgical management of a complicated temporal bone fracture. The video contains patient's medical history, preoperative radiological evaluations, and detailed surgical approach to manage the disease. The current video presents the surgical management of a complicated temporal bone fracture. The video contains patient's medical history, preoperative radiological evaluations, and detailed surgical approach to manage the disease.
MeSH term(s)	Humans ; Fractures, Bone/complications ; Fractures, Bone/diagnostic imaging ; Fractures, Bone/surgery ; Temporal Bone/diagnostic imaging ; Temporal Bone/surgery
Language	English
Publishing date	2022-12-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	604541-8
ISSN	1532-818X ; 0196-0709
ISSN (online)	1532-818X
ISSN	0196-0709
DOI	10.1016/j.amjoto.2022.103783
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Article ; Online: Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in mdx cardiomyocytes.

Nasilli, Giovanna / de Waal, Tanja M / Marchal, Gerard A / Bertoli, Giorgia / Veldkamp, Marieke W / Rothenberg, Eli / Casini, Simona / Remme, Carol Ann

Cardiovascular research

2024

Abstract: Background: The microtubule (MT) network plays a major role in the transport of the cardiac sodium channel Nav1.5 to the membrane, where the latter associates with interacting proteins such as dystrophin. Alterations in MT dynamics are known to impact ... ...

Abstract	Background: The microtubule (MT) network plays a major role in the transport of the cardiac sodium channel Nav1.5 to the membrane, where the latter associates with interacting proteins such as dystrophin. Alterations in MT dynamics are known to impact on ion channel trafficking. Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, is associated with an increase in MT detyrosination, decreased sodium current (INa), and arrhythmias. Parthenolide (PTL), a compound that decreases MT detyrosination, has shown beneficial effects on cardiac function in DMD, but its impact on INa has not been investigated. Methods and results: Ventricular cardiomyocytes (CMs) from wild-type (WT) and mdx (DMD) mice were incubated with either 10 µM PTL, 20 µM EpoY or DMSO for 3-5 hours, followed by patch-clamp analysis to assess INa and action potential (AP) characteristics in addition to immunofluorescence and stochastic optical reconstruction microscopy (STORM) to investigate MT detyrosination and Nav1.5 cluster size and density, respectively. In accordance with previous studies, we observed increased MT detyrosination, decreased INa and reduced AP upstroke velocity (Vmax) in mdx CMs compared to WT. PTL decreased MT detyrosination and significantly increased INa magnitude (without affecting INa gating properties) and AP Vmax in mdx CMs, but had no effect in WT CMs. Moreover, STORM analysis showed that in mdx CMs, Nav1.5 clusters were decreased not only in the grooves of the lateral membrane (LM; where dystrophin is localized), but also at the LM crests. PTL restored Nav1.5 clusters at the LM crests (but not the grooves), indicating a dystrophin-independent trafficking route to this subcellular domain. Interestingly, Nav1.5 cluster density was also reduced at the intercalated disc (ID) region of mdx CMs, which was restored to WT levels by PTL. Treatment of mdx CMs with EpoY, a specific MT detyrosination inhibitor, also increased INa density, while decreasing the amount of detyrosinated MTs, confirming a direct mechanistic link. Conclusions: Attenuating MT detyrosination in mdx CMs restored INa and enhanced Nav1.5 localization at the LM crest and ID. Hence, the reduced whole-cell INa density characteristic of mdx CMs is not only the consequence of the lack of dystrophin within the LM grooves, but is also due to reduced Nav1.5 at the LM crest and ID secondary to increased baseline MT detyrosination. Overall, our findings identify MT detyrosination as a potential therapeutic target for modulating INa and subcellular Nav1.5 distribution in pathophysiological conditions.
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvae043
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Article ; Online: Postinfective Modiolus Erosion after Cochlear Implantation.

Bertoli, Giulia / Guida, Maurizio / Falcioni, Maurizio

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

2021 Volume 42, Issue 9, Page(s) e1402–e1403

MeSH term(s)	Cochlea/surgery ; Cochlear Implantation ; Cochlear Implants ; Humans
Language	English
Publishing date	2021-05-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036790-9
ISSN	1537-4505 ; 1531-7129
ISSN (online)	1537-4505
ISSN	1531-7129
DOI	10.1097/MAO.0000000000003201
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Article: Potential drugs against COVID-19 revealed by gene expression profile, molecular docking and molecular dynamic simulation.

Cava, Claudia / Bertoli, Gloria / Castiglioni, Isabella

Future virology

2021

Abstract: Aim: ...

Abstract	Aim:
Language	English
Publishing date	2021-07-20
Publishing country	England
Document type	Journal Article
ISSN	1746-0794
ISSN	1746-0794
DOI	10.2217/fvl-2020-0392
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