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Article ; Online: HCN1 channels: A versatile tool for signal processing by primary sensory neurons.

Barravecchia, Ivana / Demontis, Gian Carlo

Progress in biophysics and molecular biology

2021 Volume 166, Page(s) 133–146

Abstract: Most primary sensory neurons (PSNs) generate a slowly-activating inward current in response to membrane hyperpolarization ( ... ...

Abstract	Most primary sensory neurons (PSNs) generate a slowly-activating inward current in response to membrane hyperpolarization (I
MeSH term(s)	Action Potentials ; Animals ; Humans ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Mice ; Potassium Channels ; Sensory Receptor Cells
Chemical Substances	HCN1 protein, human ; Hcn1 protein, mouse ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Potassium Channels
Language	English
Publishing date	2021-06-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209302-9
ISSN	1873-1732 ; 0079-6107
ISSN (online)	1873-1732
ISSN	0079-6107
DOI	10.1016/j.pbiomolbio.2021.06.009
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Article ; Online: Optimal low-intensity pulsed ultrasound stimulation for promoting anti-inflammatory effects in macrophages.

Iacoponi, Francesco / Cafarelli, Andrea / Fontana, Francesco / Pratellesi, Tiziano / Dumont, Erik / Barravecchia, Ivana / Angeloni, Debora / Ricotti, Leonardo

APL bioengineering

2023 Volume 7, Issue 1, Page(s) 16114

Abstract: In this paper, we stimulated M1-like macrophages (obtained from U937 cells) with low-intensity pulsed ultrasound (LIPUS) to lower pro-inflammatory cytokine production. A systematic screening of different frequencies, intensities, duty cycles, and ... ...

Abstract	In this paper, we stimulated M1-like macrophages (obtained from U937 cells) with low-intensity pulsed ultrasound (LIPUS) to lower pro-inflammatory cytokine production. A systematic screening of different frequencies, intensities, duty cycles, and exposure times was performed. The optimal stimulation conditions leading to a marked decrease in the release of inflammatory cytokines were determined to be 38 kHz, 250 mW/cm
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article
ISSN	2473-2877
ISSN (online)	2473-2877
DOI	10.1063/5.0137881
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Article ; Online: Inducible Pluripotent Stem Cells to Model and Treat Inherited Degenerative Diseases of the Outer Retina: 3D-Organoids Limitations and Bioengineering Solutions.

Andreazzoli, Massimiliano / Barravecchia, Ivana / De Cesari, Chiara / Angeloni, Debora / Demontis, Gian Carlo

Cells

2021 Volume 10, Issue 9

Abstract: Inherited retinal degenerations (IRD) affecting either photoreceptors or pigment epithelial cells cause progressive visual loss and severe disability, up to complete blindness. Retinal organoids (ROs) technologies opened up the development of human ... ...

Abstract	Inherited retinal degenerations (IRD) affecting either photoreceptors or pigment epithelial cells cause progressive visual loss and severe disability, up to complete blindness. Retinal organoids (ROs) technologies opened up the development of human inducible pluripotent stem cells (hiPSC) for disease modeling and replacement therapies. However, hiPSC-derived ROs applications to IRD presently display limited maturation and functionality, with most photoreceptors lacking well-developed outer segments (OS) and light responsiveness comparable to their adult retinal counterparts. In this review, we address for the first time the microenvironment where OS mature, i.e., the subretinal space (SRS), and discuss SRS role in photoreceptors metabolic reprogramming required for OS generation. We also address bioengineering issues to improve culture systems proficiency to promote OS maturation in hiPSC-derived ROs. This issue is crucial, as satisfying the demanding metabolic needs of photoreceptors may unleash hiPSC-derived ROs full potential for disease modeling, drug development, and replacement therapies.
MeSH term(s)	Animals ; Bioengineering/methods ; Cell Differentiation ; Humans ; Induced Pluripotent Stem Cells/cytology ; Organoids/cytology ; Retinal Degeneration/pathology ; Retinal Degeneration/therapy ; Retinal Pigment Epithelium/cytology
Language	English
Publishing date	2021-09-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10092489
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Article ; Online: Predicting potentially pathogenic effects of

Poli, Giulio / Barravecchia, Ivana / Demontis, Gian Carlo / Sodi, Andrea / Saba, Alessandro / Rizzo, Stanislao / Macchia, Marco / Tuccinardi, Tiziano

Journal of enzyme inhibition and medicinal chemistry

2022 Volume 37, Issue 1, Page(s) 1765–1772

Abstract: The human retinal pigment epithelium-specific 65-kDa protein ( ...

Abstract	The human retinal pigment epithelium-specific 65-kDa protein (
MeSH term(s)	Humans ; Molecular Dynamics Simulation ; Mutation, Missense ; Retinitis Pigmentosa/genetics ; cis-trans-Isomerases/genetics
Chemical Substances	retinoid isomerohydrolase (EC 3.1.1.64) ; cis-trans-Isomerases (EC 5.2.-)
Language	English
Publishing date	2022-06-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2082578-X
ISSN	1475-6374 ; 1475-6366
ISSN (online)	1475-6374
ISSN	1475-6366
DOI	10.1080/14756366.2022.2090547
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Article ; Online: Top-Down Proteomics of Human Saliva, Analyzed with Logistic Regression and Machine Learning Methods, Reveal Molecular Signatures of Ovarian Cancer.

Scebba, Francesca / Salvadori, Stefano / Cateni, Silvia / Mantellini, Paola / Carozzi, Francesca / Bisanzi, Simonetta / Sani, Cristina / Robotti, Marzia / Barravecchia, Ivana / Martella, Francesca / Colla, Valentina / Angeloni, Debora

International journal of molecular sciences

2023 Volume 24, Issue 21

Abstract: Ovarian cancer (OC) is the most lethal of all gynecological cancers. Due to vague symptoms, OC is mostly detected at advanced stages, with a 5-year survival rate (SR) of only 30%; diagnosis at stage I increases the 5-year SR to 90%, suggesting that early ...

Abstract	Ovarian cancer (OC) is the most lethal of all gynecological cancers. Due to vague symptoms, OC is mostly detected at advanced stages, with a 5-year survival rate (SR) of only 30%; diagnosis at stage I increases the 5-year SR to 90%, suggesting that early diagnosis is essential to cure OC. Currently, the clinical need for an early, reliable diagnostic test for OC screening remains unmet; indeed, screening is not even recommended for healthy women with no familial history of OC for fear of post-screening adverse events. Salivary diagnostics is considered a major resource for diagnostics of the future. In this work, we searched for OC biomarkers (BMs) by comparing saliva samples of patients with various stages of OC, breast cancer (BC) patients, and healthy subjects using an unbiased, high-throughput proteomics approach. We analyzed the results using both logistic regression (LR) and machine learning (ML) for pattern analysis and variable selection to highlight molecular signatures for OC and BC diagnosis and possibly re-classification. Here, we show that saliva is an informative test fluid for an unbiased proteomic search of candidate BMs for identifying OC patients. Although we were not able to fully exploit the potential of ML methods due to the small sample size of our study, LR and ML provided patterns of candidate BMs that are now available for further validation analysis in the relevant population and for biochemical identification.
MeSH term(s)	Humans ; Female ; Saliva ; Proteomics/methods ; Logistic Models ; Ovarian Neoplasms/diagnosis ; Biomarkers, Tumor ; Machine Learning
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2023-10-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242115716
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Article ; Online: Increasing cell culture density during a developmental window prevents fated rod precursors derailment toward hybrid rod-glia cells.

Barravecchia, Ivana / De Cesari, Chiara / Guadagni, Viviana / Signore, Giovanni / Bertolini, Edoardo / Giannelli, Serena Gea / Scebba, Francesca / Martini, Davide / Pè, Mario Enrico / Broccoli, Vania / Andreazzoli, Massimiliano / Angeloni, Debora / Demontis, Gian Carlo

Scientific reports

2023 Volume 13, Issue 1, Page(s) 6025

Abstract: In proliferating multipotent retinal progenitors, transcription factors dynamics set the fate of postmitotic daughter cells, but postmitotic cell fate plasticity driven by extrinsic factors remains controversial. Transcriptome analysis reveals the ... ...

Abstract	In proliferating multipotent retinal progenitors, transcription factors dynamics set the fate of postmitotic daughter cells, but postmitotic cell fate plasticity driven by extrinsic factors remains controversial. Transcriptome analysis reveals the concurrent expression by postmitotic rod precursors of genes critical for the Müller glia cell fate, which are rarely generated from terminally-dividing progenitors as a pair with rod precursors. By combining gene expression and functional characterisation in single cultured rod precursors, we identified a time-restricted window where increasing cell culture density switches off the expression of genes critical for Müller glial cells. Intriguingly, rod precursors in low cell culture density maintain the expression of genes of rod and glial cell fate and develop a mixed rod/Muller glial cells electrophysiological fingerprint, revealing rods derailment toward a hybrid rod-glial phenotype. The notion of cell culture density as an extrinsic factor critical for preventing rod-fated cells diversion toward a hybrid cell state may explain the occurrence of hybrid rod/MG cells in the adult retina and provide a strategy to improve engraftment yield in regenerative approaches to retinal degenerative disease by stabilising the fate of grafted rod precursors.
MeSH term(s)	Retina/metabolism ; Neuroglia/metabolism ; Cell Differentiation/genetics ; Transcription Factors/metabolism ; Cell Culture Techniques
Chemical Substances	Transcription Factors
Language	English
Publishing date	2023-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-32571-y
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Article ; Online: Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

Barravecchia, Ivana / Lee, Jennifer M / Manassa, Jason / Magnuson, Brian / Ferris, Sarah F / Cavanaugh, Sophia / Steele, Nina G / Espinoza, Carlos E / Galban, Craig J / Ramnath, Nithya / Frankel, Timothy L / Pasca di Magliano, Marina / Galban, Stefanie

Molecular cancer research : MCR

2023 Volume 22, Issue 3, Page(s) 295–307

Abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-to-mesenchymal transition (EMT), and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis lung carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, preexisting fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of EMT. Implications: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.
MeSH term(s)	Humans ; Animals ; Mice ; Lung Neoplasms/genetics ; Pandemics ; Idiopathic Pulmonary Fibrosis/genetics ; Bleomycin/toxicity ; COVID-19 ; Tumor Microenvironment
Chemical Substances	Bleomycin (11056-06-7)
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-23-0480
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Article ; Online: Histone H3 K27M-mediated regulation of cancer cell stemness and differentiation in diffuse midline glioma.

Sharma, Monika / Barravecchia, Ivana / Magnuson, Brian / Ferris, Sarah F / Apfelbaum, April / Mbah, Nneka E / Cruz, Jeanette / Krishnamoorthy, Varunkumar / Teis, Robert / Kauss, McKenzie / Koschmann, Carl / Lyssiotis, Costas A / Ljungman, Mats / Galban, Stefanie

Neoplasia (New York, N.Y.)

2023 Volume 44, Page(s) 100931

Abstract: Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG ... ...

Abstract	Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG biopsies. We hypothesized that ALDH-mediated stemness and resistance may in part be driven by the oncohistone itself. Upon deletion of H3K27M, ALDH1A3 expression decreased dramatically and was accompanied by a gain in astrocytic marker expression and a loss of neurosphere forming potential, indicative of differentiation. Here we show that the oncohistone regulates histone acetylation through ALDH1A3 in a Wnt-dependent manner and that loss of H3K27M expression results in sensitization of DMGs to radiotherapy. The observed elevated Wnt signaling in H3K27M-altered DMG likely stems from a dramatic suppression of mRNA and protein expression of the Wnt inhibitor EYA4 driven by the oncohistone. Thus, our findings identify EYA4 as a bona fide tumor suppressor in DMG that upon suppression, results in aberrant Wnt signaling to orchestrate stemness and differentiation. Future studies will explore whether overexpression of EYA4 in DMG can impede growth and invasion. In summary, we have gained mechanistic insight into H3K27M-mediated regulation of cancer stemness and differentiation, which provides rationale for exploring new therapeutic targets for DMG.
MeSH term(s)	Humans ; Histones/metabolism ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Cell Differentiation/genetics ; Glioma/pathology ; Glioma/genetics ; Glioma/metabolism ; Wnt Signaling Pathway ; Cell Line, Tumor ; Mice ; Gene Expression Regulation, Neoplastic ; Animals ; Brain Neoplasms/pathology ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Methylation
Chemical Substances	Histones
Language	English
Publishing date	2023-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2023.100931
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Article: WITHDRAWN: Oncogenic KRAS

Lasse-Opsahl, Emily / Baliira, Rachael / Barravecchia, Ivana / McLintock, Elyse / Lee, Jennifer M / Ferris, Sarah F / Espinoza, Carlos E / Hinshaw, Rachael / Cavanaugh, Sophia / Robotti, Marzia / Brown, Kristee / Donahue, Katelyn / Abdelmalak, Kristena Y / Galban, Craig J / Frankel, Timothy L / Zhang, Yaqing / di Magliano, Marina Pasca / Galban, Stefanie

bioRxiv : the preprint server for biology

2024

Abstract: This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. ...

Abstract	This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.
Language	English
Publishing date	2024-02-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.16.568090
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Article ; Online: Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

Sharma, Monika / Barravecchia, Ivana / Teis, Robert / Cruz, Jeanette / Mumby, Rachel / Ziemke, Elizabeth K / Espinoza, Carlos E / Krishnamoorthy, Varunkumar / Magnuson, Brian / Ljungman, Mats / Koschmann, Carl / Chandra, Joya / Whitehead, Christopher E / Sebolt-Leopold, Judith S / Galban, Stefanie

Molecular cancer therapeutics

2023 Volume 23, Issue 1, Page(s) 24–34

Abstract: Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. ... ...

Abstract	Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
MeSH term(s)	Humans ; Child ; Mice ; Animals ; Diffuse Intrinsic Pontine Glioma/drug therapy ; Diffuse Intrinsic Pontine Glioma/genetics ; Diffuse Intrinsic Pontine Glioma/metabolism ; Neoplasm Recurrence, Local ; DNA Repair ; Signal Transduction ; DNA/therapeutic use ; Brain Stem Neoplasms/drug therapy ; Brain Stem Neoplasms/genetics ; Brain Stem Neoplasms/pathology
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0026
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