PhD projects and EU funds
PNRR Projects
Below you can find information on the projects financed by the funds of the National Recovery and Resilience Plan (PNRR)
DD n. 931
PhD Program: Molecular Medicine
PhD Student: Sara Pozzi
Supervisor: Samuel Zambrano
Abstract
Resistance to cancer therapy is a multifaceted problem. Non-genetic heterogeneity is recognized as a driving factor in the emergence of drug-resistant populations: the transcription factor (TF) p53, a tumor suppressor activated upon DNA damage, plays a central role in this context, since p53 activation dynamics in response to therapy is thought to drive cell fate decision. Here we aim to combine live cell imaging, molecular biology and advanced data analysis to determine to what extent p53 dynamics is predictive of the response to therapy in colorectal cancer (CRC) cell lines and in patient-derived organoids (PDOs).
Objectives:
To develop an image and data analysis pipeline able to predict CRC cells response to therapy in live cell imaging experiments. This system will then be extended to the analysis of the response of PDOs to chemotherapies.
Results achieved
The results obtained show that genotoxic chemotherepies activate p53 in our colorectal cancer cell line HCT116-p53GFP, and that the cells surviving to the first days of therapy display higher p53 accumulation. Moreover, it seems that cells resistant to long-term treatments display constitutively higher levels of p53. We are currently investigating the mechanisms that lead to the stabilization of p53 levels, in order to correlate the dynamics of p53 with the development of resistant phenotype.
PNC MUR Investment I.1 – Notice D.D. 931 of 06/06/2022 – Call for the allocation of funding for research initiatives focused on technologies and innovative approaches in the healthcare and assistance sectors.
PhD Program: Molecular Medicine
PhD Student: Martina Leone
Supervisor:Paola Falletta
Abstract
The Integrated Stress Response (ISR) is an adaptive signaling pathway that senses and responds to microenvironmental cues. Cancer cells hijack ISR to promote metastasis and drug resistance. Our project aims to dissect the mechanism by which ISR drives Colorectal Cancer (CRC) aggressiveness to define new targetable vulnerabilities, and measure ISR activation in CRC Patient-Derived Organoids to predict clinical response to therapies and provide data to Artificial Intelligence-based digital models
Objectives
The identification of events triggered by the transcriptional and translational reprogramming induced by ISR that lead to metastatic potential and drug resistance in CRC.
Results achieved
During the first year of my PhD, I identified an interplay between ISR and KRAS, the most frequently mutated oncogene in CRC. In particular, in 2D and 3D models of CRC cell lines, including Patient Derived Organoids (PDOs), activation of ISR leads to the activation of the KRAS signaling cascade. Furthermore, a role of ISR in determining CRC metastatic potential by driving invasiveness and resistance to the first line chemotherapy regimens for metastatic CRC was demonstrated.
PNC MUR Investment I.1 – Notice D.D. 931 of 06/06/2022 – Call for the allocation of funding for research initiatives focused on technologies and innovative approaches in the healthcare and assistance sectors.
PhD Program: Molecular Medicine
PhD Student: Tommaso Russo
Supervisor:Francesco De Cobelli
Abstract
Colorectal Cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related deaths. Survival is primarily determined by the disease stage and the presence of metastasis. The combination of chemotherapy and liver resection remains the therapeutic option with the highest survival benefit for patients with colorectal liver metastases (CRLM). There is a clinical need to identify in advance patients who have different probabilities of developing disease recurrence after locoregional treatment (liver resection ± thermal ablation) and differing responses to chemotherapy. This would allow for a risk-based allocation of treatments and resources. As is known, Artificial Intelligence (AI) is a branch of computer science aimed at simulating human intelligence and behaviors to assist humans in specific tasks. In the context of the PNRR-funded D3-4HEALTH call, Spoke 2 focuses on liver metastases from colorectal cancer. The goal is to collect imaging, clinical, and biological data, and train machine learning models to predict recurrence time, creating an algorithm based on data available at diagnosis to accurately predict treatment response, the likelihood of developing metastases not visible in routine radiological exams, and to assess whether radiomic features of the microenvironment around visible metastases can predict the occurrence of new metastases or progression-free survival.
Objectives
Identify patients at risk of recurrence to avoid futile surgeries ; Identify patients who respond pharmacologically; Timing of overall survival and progression-free survival; Prediction of recurrence and the onset of micrometastases ; Use of the microenvironment to predict metastasis occurrence and the best medical therapy
Results achieved
Preliminary results are not yet available. We have selected a cohort of 1,221 patients with primary colon tumors and at least one liver metastasis, all of whom underwent curative liver surgery. We have analyzed 150 patients from the LIMET database. From this population, 10 patients were excluded. We have extracted data from 17 patients who had CT and MRI images performed no more than 45 days before liver resection surgery. These numbers are explained by the high number of patients who undergo imaging at other hospitals before surgery at San Raffaele Hospital, making image collection quite difficult. We have started manually segmenting liver lesions to extract radiomic features in a group of 30 test patients using both 3D Slicer (an open-source software) and the commercial software MIM to assess reproducibility and feature stability through intra-class correlation. Additionally, we have begun segmenting the entire non-metastatic liver parenchyma using the "Total Segmentator" extension in 3D Slicer. At the same time, we are developing the reporting module to define all the radiological variables to be collected during segmentation (e.g., diameters, density, distance from blood vessels, etc.).
PNC MUR Investment I.1 – Notice D.D. 931 of 06/06/2022 – Call for the allocation of funding for research initiatives focused on technologies and innovative approaches in the healthcare and assistance sectors.
PhD Program: Molecular Medicine
PhD Student: Gabriele Metalli
Supervisor:Giovanni Tonon
Abstract
Understanding and countering cancer resistance remains the most significant challenge in
oncology. Despite advanced new therapies, first-line treatment for many cancer types remains
chemotherapy, yet the mechanisms behind tumor cell resistance remain unclear. We propose that chemotherapy resistance stems from epigenetic modifications and suggest a strategy to prevent and reverse these changes by interfering with the emergence of resistance.
Objectives
Our objective is to leverage genomic biobanks of patient-derived organoids and microfluidic platforms for drug screening to evaluate transcriptional states and identify epigenetic modifiers affecting tumor development. We expect to identify key modifiers and assess chemotherapy response, integrating this data with AI approaches at San Raffaele.
Results achieved
We demonstrated that therapy resistance is not caused by clonal evolution and that chemotherapy induces an epigenetic remodelling of the chromatin. Next we are going to identify key epigenetic players via CRISPR/Cas9-based screening.
PNC MUR Investment I.1 – Notice D.D. 931 of 06/06/2022 – Call for the allocation of funding for research initiatives focused on technologies and innovative approaches in the healthcare and assistance sectors.
PhD Program: Molecular Medicine
PhD Student: Chiara Ceriani
Supervisor: Lorenzo Piemonti
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that destroys insulin-producing β cells in the pancreas. While T1D can be managed with insulin, no treatment exists to control autoreactive T cells and prevent β cell destruction. A potential cure is represented by β cell replacement therapy that uses allogeneic islets or pancreas from cadaveric donors, but this poses immunological challenges. Stem cell-based therapies and EVs show promise in reducing autoimmune reactions and improving β cell replacement success. Inducing immunological tolerance, especially using tolerogenic Extracellular Vesicles (EVs), could prevent the disease or enhance β cell replacement therapy outcomes
Objectives:
The project aims to use EVs from induced pluripotent stem cells (iPSCs) and iPSC-derived β cells to induce tolerance in Type 1 Diabetes. It involves determining the expression of immunogenic/tolerogenic molecules in iPSCs and EVs, assessing their impact on human T cells, and examining EVs in vivo and in an in vitro biological effect.
Results achieved
To date, I have developed an efficient method to isolate extracellular vesicles (EVs) from iPSCs and iPSC-derived β cells (iβ). I analyzed the expression of immunogenic/tolerogenic molecules, observing tolerogenic markers in both cell lines. I then characterized EVs, demonstrating the presence of iPSC and iβ markers, as well as typical EVs markers. Additionally, I induced the expression of HLA-A2 in iPSCs, which was maintained in both iβ and EVs, thus creating an in vitro model to study the effect of EVs on human T cells.
PNC MUR Investment I.1 – Notice D.D. 931 of 06/06/2022 – Call for the allocation of funding for research initiatives focused on technologies and innovative approaches in the healthcare and assistance sectors.
DM n. 117
PhD Program: Molecular Medicine
PhD Student: Eva Baronchelli
Supervisor: Vania Broccoli
Abstract
Glioblastoma multiforme is the most common and lethal brain cancer in adults. Despite current treatments, virtually all patients relapse due to the presence of cancer stem cells (CSCs) that can self-renew and regenerate the tumor, remaining quiescent or exhibiting low proliferative activity. In order to target residual CSCs, my laboratory generated a SOX2 epigenetic silencer able to switch off the SOX2 downstream oncogenic gene network and suppress tumor relapses.
Likewise, the aim of this project is to establish another epigenetic silencing factor called TES to switch off the YAP/TAZ oncogenic transcriptional cascade which drives tumor malignancy.
Results achieved
TES silences the TEAD1-YAP/TAZ oncogenic transcriptional network in GBM cells, thereby curbing GBM malignancy. Notably, TES induces a robust transcriptional silencing of a large group of YAP/TAZ targets genes by the induction of stable epigenetic modifications. Moreover, TES promotes high cell death and reduction of migration in glioma cell lines and in patient-derived GBM CSCs. In accordance, local viral delivery of TES in orthotopic intracranial mouse xenograft repressed the development of the human GBM-like masses.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Linda Bossini
Supervisor: Alessandro Sessa
Abstract
This project aims to exploit a newly developed murine model that conditionally overexpresses the human mutated SET binding protein 1 (SETBP1) gene through a Cre-mediated system, to delineate the in vivo consequences of its accumulation. The availability of a reliable in vivo model that faithfully recapitulates the main features of the disease serves as a powerful tool to enhance our understanding of Schinzel-Giedion syndrome (SGS) pathogenesis while providing a valuable platform for testing potential therapeutic approaches.
Objectives
Our approach involves addressing this biological question adopting a complementary approach to spatially and temporally define the origin of the pathological phenotype. This comprehensive investigation may offer insights into the potential reversibility of the disease's symptoms.
Results achieved
To pinpoint the cellular origins of SGS pathological phenotypes, including epilepsy, we generated a whole-brain disease model alongside excitatory-specific and inhibitory-specific mutant lines. Preliminary morphological analyses suggest hippocampal impairments, highlighting its central role in the phenotype. Electrophysiological studies confirm alterations in synaptic plasticity within the classic hippocampal circuitry. Next steps will involve single-cell approaches to molecularly profile the affected cellular populations.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Paolo Camisa
Supervisor: Stefano Crippa
Abstract
Pancreatic cancer (PC) is among the deadliest solid tumors and is often resistant to traditional chemotherapy due to a complex and heterogeneous tumor microenvironment. This study proposes a new mesenchymal stem cell (MSC)-based drug delivery system to target tumors more effectively, potentially reducing systemic toxicity and enhancing anti-tumoral activity. MSCs can migrate to tumors, alter neighboring cell signaling, and deliver anticancer drugs, inducing tumor regression and reprogramming the tumor microenvironment.
Objectives
Investigate the effects of MSC-based therapy on metastatic PDAC progression, tumor microenvironment, and immune response, and evaluate its feasibility in clinical trials.
Results achieved
To date, we have demonstrated that mesenchymal stem cells can be easily loaded with chemotherapeutic drugs effective against pancreatic cancer. After administration, these cells remain at the metastasis site—in our model, the liver—for about a week, leading to a significant slowdown in tumor growth while causing less systemic toxicity compared to traditional chemotherapy.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Calogero Carlino
Supervisor: Davide Cittaro
Abstract:
Cancer is a complex disease, in which aneuploidies and microenvironment alterations are considered major drivers of development and progression. Recent progress in spatial multi omics enable the study of cancer in its microenvironment, offering new opportunity to dissect the interaction between aneuploidy and tumor microenvironment. The high complexity and sparsity of current multi omics readouts require reliable algorithms for the analysis, and mathematical abstraction for data integration.
Objectives
We will develop explainable probabilistic models to predict tumor aneuploidy from spatial omics data, with the aim to study the biological mechanisms that govern the emergence and evolution of cancer
Results achieved
During the first year of my PhD we performed an extensive benchmark of state-of-the-art methods to identify CNAs from scRNA-seq data. Inspired by some of them, we implemented a Hidden Markov Model able to perform loss of heterozygosity (LoH) inference on bulk transcriptomics data. We are now working on enabling single cell or single spatial spot prediction of CNAs in our models. We also started to study and apply methods borrowed from network science and topology to spatial transcriptomics data, with the aim of modeling the reciprocal influence between specific CNAs and the tumor microenvironment.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student:Irina Cutei
Supervisor:Vania Broccoli
Abstract
PRR12 is a neglected gene, whose haploinsufficiency has been recently associated with neurodevelopmental and eye abnormalities. Its function is still unknown. In our project we plan to investigate the molecular mechanisms of action underlying the pathogenic effects of PRR12 haploinsufficiency, and so to gain new insight into the role of the gene. To do so, we will create a Knock-Out stable cell line and a Loss-Of-Function mouse line.
Objectives
Our hypothesis is that PRR12 might play an important role as epigenetic regulator in neurodevelopment. We will test this performing gene expression and DNA methylation studies on our KO and LOF models.
Results achieved
In the first year, we developed in vitro and in vivo models to study the function of Prr12. In vitro, the CRISPR/Cas9 system was used to introduce mutations in exon 8 of the gene, generating mutant cell lines validated through NGS and expression studies. In vivo, a mouse model was generated by inserting LoxP sequences flanking exon 6 of the gene. By crossing this model with lines expressing Cre recombinase either systemically or exclusively in the nervous system, we induced nonsense-mediated mRNA decay of the transcript.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: RacheleD’Amore
Supervisor: Alessandro Aiuti
Abstract
Alpha-mannosidosis (α-MAN) is an inherited lysosomal storage disorder (LSD) that leads to progressive skeletal, immunological and neurological impairments. Hematopoietic stem/progenitor cells (HSPC) transplantation and enzyme replacement therapy are the standard of care for α-MAN but incompletely correct the disease skeletal and neurological phenotype. It was previously showed in two types of LSDs that HSPC- Gene therapy (GT) is able to correct non-hematopoietic tissues, including CNS and bones. Our goal is to generate pre-clinical evidence for the development of HSPC-GT for α-MAN by exploiting a MAN2B1-/- mouse model that we are currently characterizing at skeletal and neurological level.
Results achieved
Our data show that the MAN2B1-/- (KO) murine model displays no MAN2B activity in liver and bone marrow (BM) and a higher oligosaccharides accumulation in plasma and urines than wild-type (WT) littermates. Additionally, neuronal cytoplasmic vacuolations were detected in KO mice brains, associated with reduced motor coordination at 4 months. The skeletal evaluations show alterations in long bones length and bone mineralization in KO mice with respect to WT. Moreover, immunophenotypic analyses of 4-months-old KO female mice reveal a higher number of lymphocytes and granulocyte-monocyte-lymphoid progenitors in the BM, but no differences in the peripheral blood, with respect to WT mice.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Francesco Di Mauro
Supervisor:Giuseppina Arbone
Abstract
Esophageal adenocarcinoma (EAC) is a highly aggressive tumor, treated with neoadjuvant chemotherapy (nCT), for which only 20% of patients achieve a pathological complete response. We have recently demonstrated that the baseline immune microenvironment is correlated with therapy response. We hypothesize that the response to nCT might result from the stimulation of a local T cell response against tumor neoantigens (TNAs).
Objectives
The aim of my project is to define the breadth and dynamics of TNAs-specific T cell responses (from blood and tumor) in patients with EAC, comparing responders versus non-responders to nCT
Results achieved
Tumor-specific T cells have been enriched and expanded both from the blood and the lymph node of an esophageal adenocarcinoma complete responder patient. The analysis of the blood and the tumor draining lymph node of this patient highlighted a strong and shared T cell response against one or more of the predicted tumor neoantigens. Tumor neoepitope-specific T cell receptors were reconstructed by TCR sequencing and will be validated in vitro via functional assays.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student:Martina Mainardi
Supervisor: Gaia Colasante
Abstract
Dravet Syndrome (DS) is an infantile epileptic encephalopathy characterized by drug resistant seizures, cognitive impairment, and high risk of mortality. It is caused by mutations in SCN1A gene encoding the alpha subunit of the sodium channel Nav1.1. DS is considered to be caused by inhibitory neurons hypoexcitability, but secondary circuit modifications contribute to disease progression and information on the optimal neuronal populations to target at different disease stages is lacking..
Objectives
The project aims to reactivate Scn1a gene expression only in inhibitory neurons in a DS mouse model at different disease stages to assess whether targeting them is actually sufficient to recover DS symptoms.
Results achieved
My PhD project focuses on assessing the impact of Scn1a gene reactivation in interneurons on the phenotype of Dravet Syndrome. We started addressing the constitutive restoration of the expression of the gene in the selected cellular population exploiting a transgenic murine line, mimicking a preventive therapy. The results we obtained so far point to a dramatic improvement of the epileptic phenotype of mice with only few spontaneous seizures still persisting. We are now better investigating these epileptic events to understand their nature. Meanwhile, we are starting to correct interneurons in adult mice after the onset of symptoms to mimic an actual gene therapy treatment.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student:Francesca Marzuttini
Supervisor: Eliana Ruggiero
Abstract
The final aim of this project is to generate a T cell receptor (TCR)-redirected T cells-based immunotherapy for acute myeloid leukemia (AML) treatment. High throughput sequencing technologies, immune repertoire profiling and in vitro immunological functional assays will be employed to identify and validate novel tumor-specific TCRs from AML patients’ samples. Newly identified TCRs will be used to re-address T cell specificity towards the tumor by TCR gene editing approach. The safety, the efficacy of the TCR-engineered T cells and the dissection of the players involved in the co-evolution of T cell/tumor interactions will be further addressed in vitro and in vivo in the last aim of the project.
Results obtained in this project will lead to the generation of living drugs to be tested as novel therapeutic options for AML patients.
Results achieved
We conducted single-cell multiomic analysis on CD8+ T cells isolated from the peripheral blood of transplanted AML patients utilizing barcoded dextramers to label antitumoral lymphocytes. Unsupervised clustering of sequencing data identified distinct transcriptional subsets of T cells, each associated with different metabolic profiles and activation/functional status. Interestingly, we observed a predominance of antitumoral lymphocytes within specific clusters. Based on their transcriptional signatures, key antitumoral TCRs were selected for subsequent functional validation.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Francesca Nicola
Supervisor:Daniela Maria Cirillo
Abstract
Non-tuberculous mycobacteria (NTM) have emerged as a major threat to the health of individuals with cystic fibrosis (CF), bronchiectasis and other immunocompromised patients. The mechanisms of infection and resistance are poorly understood. It is urgent to deepen our understanding of pathogenicity to develop personalized treatments and prevent severe lung damage. My PhD project aims to elucidate the immune mechanisms in response to Mycobacterium abscessus (Mabs) infection and persistence, identifying new therapeutic targets to mitigate disease progression.
Objectives
To achieve a more comprehensive understanding of immune mechanisms counteracting Mabs infection and persistence, we will clarify the role of mucosal immune response in disease progression and host-bacteria interaction at the cellular level.
Results achieved
We analyzed 11 Mycobacterium abscessus (Mabs) isolates from 5 cystic fibrosis patients, focusing on morphotype and genome. The morphotype emerged as the main factor influencing the infection, with over 2,000 host genes differentially expressed and the release of IL-6 and IL-8. Two strains, one smooth and one rough, were tested on human bronchial epithelial cells in an air-liquid interface (ALI) model, revealing transcriptomic differences through single-cell RNA sequencing. Basal and secretory cells appeared to be the most involved. Rough strains triggered stronger immune responses, highlighting the impact of morphotype on infection.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Alessandro Romano
Supervisor: Alessandra Mortellaro
Abstract
Nod-like receptors (NLRs) are multiprotein complexes that, under inflammatory conditions,
stimulate the secretion of pro-inflammatory cytokines and trigger cell death. Yet, their role in
hematopoiesis needs to be understood. This project seeks to elucidate the contribution of NLRs to hematopoiesis, focusing on their impact on hematopoietic stem and progenitors cells (HSPCs) in both physiological and inflammatory conditions.
Objectives
We aim to determine whether NLRs play a role in the maintenance and diNerentiation of the hematopoietic stem cell-progenitor cell pool in acute and chronic inflammatory diseases
Results achieved
We revealed that hematopoietic stem/progenitor cells (HSPCs) lacking NLRP3 or GSDMD fail to secrete IL-1β, suggesting impaired cytokine processing and release. In addition, cell death analysis showed reduced pyroptotic cell death in Nlrp3- and Gsdmd-deficient HSPCs, accompanied by increased apoptosis. Additionally, immunophenotypic analysis showed that under acute inflammation, GSDMD deficiency reduces bone marrow HSPC number and causes an expansion of myeloid and B-cell populations.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Giuseppe Suanno
Supervisor: Giulio Ferrari
Abstract
The cornea is the most densely innervated tissue in the human body. Most ocular surface diseases have been associated with altered corneal nerve morphology and function. While these abnormalities have been widely described, their impact on wound healing and inflammation has just started to emerge. In addition, the role of aging on nerve function/morphology and its subsequent impact on corneal inflammation and wound healing remains largely unexplored.
Obiettivi
The project will focus on the impact of age and injury on corneal nerve function, morphology, and phenotype. This project will provide crucial information to identify therapeutic targets and inform personalized treatments aimed at alleviating highly prevalent ocular diseases.
Results achieved
The results achieved show an aging-dependent decrease in the innervation of the corneal epithelium associated with a significant reduction in corneal mechanical and chemical sensitivity. These changes are associated with worsened ocular surface integrity and homeostasis. Interestingly, it seems that the ablation of the neuropeptide Substance P boosts and accelerates the age-dependent effects through alterations of neurotrophic and neurosensorial factors.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Bazezew Yenew Tessema
Supervisor: Daniela Maria Cirillo
Abstract
The clinical management of non-muscle-invasive bladder cancer (NMIBC) is challenging due to high recurrence and progression rates. Intravesical BCG is the gold standard for high-grade NMIBC, but only 50% of patients fully respond, and over 10% experience mild to severe side effects. Consequently, long-term follow-up with multiple tests and maintenance treatments is needed, resulting in additional healthcare costs.
Objectives
This project aims to characterize mycobacterial extracellular vesicles (MEVs) and use them as diagnostic/prognostic biomarkers and a safer alternative therapy for NMIBC. MEVs may also address the limitations related to BCG shortages.
Results achieved
BCa cell lines (BCaCL) and polarized THP-1-derived macrophages were exposed to increasing doses of non-virulent and virulent MEVs. The cytotoxic effects were observed and found to be dose-dependent when H37Rv-MEVs were used. MEVs derived from non-virulent mycobacteria (M. gordonae and BCG) showed a similar cytotoxic effect. The cytotoxic impact on polarized THP-1-derived macrophages is still under evaluation, as recent studies suggest that bacterial EVs can induce hyperactivation in macrophages. Additionally, proteomic analysis revealed the activation of a few specific pathways in vivo, which are not triggered by live BCG. The downstream effects of these pathways are currently being investigated.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Molecular Medicine
PhD Student: Alessia Ugolini
Supervisor:Chiara Bonini
Abstract
In this project we aim at developing and comparing different strategies to increase the lifespan of CAR-T regulatory cells. CAR-Tregs will be generated according to protocols already developed and tested in the lab. We will study CAR-Treg dynamics and persistence in a humanized mouse model, exploiting an in vivo imaging system, addressing so the kinetic of the cells in the presence of different human stimuli.
Objectives
Based on results of the in vivo model, we will set-up different novel strategies to prolong Treg persistence by exploiting cytokine signaling pathways or improving the cells phenotype
Results achieved
During the first year of my PhD, I could assess CAR-Treg persistence in vivo in a humanized mouse model. Infused cells have been tracked both through in vivo imaging technologies and cytofluorimetric analysis. Thanks to this experiment I could confirm CAR-Treg reduced persistence in vivo. Moreover, I could also compare different expansion protocols to find the best manufacturing method for CAR-Tregs.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Philosophy
PhD Student: Benedetta Angela Maria Carraro
Supervisor: Francesca Pola
Abstract:
The project is intended to develop research dedicated to Key enabling technologies (KETs) for the enhancement, conservation and knowledge of the historical-artistic heritage of Villa Pisani in Bagnolo di Lonigo (VI), a stratified UNESCO heritage site and a hub for cultural events and initiatives, with a multi-year program of contemporary art exhibitions. The project is part of the NRRP Mission “From Research to Business”, NextGenerationEU, and involves collaboration with the Cultural Association Villa Pisani Contemporary Art and startup company RAD HUB S.r.l.
Objectives:
The main objective of the project is to improve the visitor experience and accessibility of the stratified site in an innovative key, adopting a human-centric perspective, ensuring more engaging, inclusive and sustainable solutions.
Results achieved
The theoretical research has developed a comprehensive conceptual and methodological framework, including a critical review of KETs for stratified historical-artistic heritage and real-time monitoring of Artificial Intelligence and UNESCO’s institutional framework. The applied research, in collaboration with RAD HUB S.r.l., focused on the digitalization of the site, leading to the development of an archiving system as an infrastructure for innovative human-centric solutions.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
PhD Program: Philosophy
PhD Student: Benedetta Minardi
Supervisor: Francesca Pola
Abstract:
The research focuses on identifying potential applications of Key Enabling Technologies (KET) to enhance accessibility to contemporary sculpture archives, with particular attention
given to the Andrea Cascella Archive in Milan. The project falls within the NRRP mission "From Research to Business", NextGenerationEU, and benefits from the collaboration with
the company Zenit Arti Audiovisive.
Objectives
The project aims to improve the preservation, enhancement, and accessibility of contemporary sculpture archives by using key enabling technologies and the development of innovative solutions based on in-depth historical and artistic knowledge.
Results achieved
During the first year, innovative approaches and methodologies for the digital enhancement of archival materials were identified, thereby establishing a solid foundation for the transformation of the Andrea Cascella Archive into a pioneering model for the management of contemporary sculpture archives. In collaboration with Zenit Arti Audiovisive, a systematic cataloguing of archival materials is being conducted, with the objective of establishing an online digital platform that integrates diverse contents. A significant outcome was the "Incastri Vitali" exhibition at Rossini Art Site, which presented a concrete example of the valorization and reinterpretation of Cascella's work.
Ministerial Decree of March 2, 2023, No. 117, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
DM n. 118
PhD Program: Philosophy
PhD Student: Diletta Caimmi
Supervisor: Francesca Pola
Abstract:
This project aims to focus on virtuous institutional and para-institutional practices for the dissemination of material and immaterial cultural heritage in an inclusive, participatory, and territorially responsible way. In particular, in the selection of reference case studies, attention will be paid to entities that orient their proposals according to an ecological, feminist, and decolonial sensitivity.
Objectives:
The goal is to develop operational strategies to enhance the transformative impact of artistic practice on society, in line with the objectives set out in the Faro Convention of 2005.
Results achieved
After gathering materials to reconstruct the status quaestionis and reference literature on innovative institutional models addressing global challenges such as the ecological crisis, feminist epistemologies, and inclusivity toward marginalized communities, I began my research period at Studio Azzurro STRIAZ at Fabbrica del Vapore. I also carried out several missions to initiate dialogues and field research with various Italian entities, among which the most significant was Centrale FIES in Dro.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Elena Costa
Supervisor: Francesco Valagussa
Abstract
The current research project aims to investigate the relational dimension inherent in museums developing and exploring into some simmelian insights, bridging aesthetic-philosophical reflection with the landscape of contemporary museology.
Objectives:
The purpose of this research is to formulate an original reflection on the development of the museum institution from a mere exhibition space to a relational space
Results achieved
Results Achieved
During the first year, the dual nature of museums as both exhibition and relational spaces was investigated, confirming the growing relevance of the latter in contemporary times.
From a theoretical perspective, exploring the ideas of Georg Simmel and Walter Benjamin proved particularly useful. From an empirical perspective, the research period at Direzione regionale Musei nazionali Lombardia is substantiating the importance of the relational dimension in museums.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Cristina Ganz
Supervisor: Claudia Bianchi
Abstract
The project focuses on gender inequalities in the field of healthcare. In particular, it focuses on the interaction between health professionals and pregnant, parturient, and postpartum women during antenatal care, labour, delivery and postpartum care. The aim is to identify problematic elements in this interaction that lead to misunderstandings and sometimes compromise the quality of obstetric care.
Objectives:
The aim is to identify communicative strategies to improve the effectiveness of obstetric care and the satisfaction of the women receiving care, thereby reducing the likelihood of misunderstandings and concerns.
Results achieved:
During the first year of the doctoral programme, qualitative data were collected to analyse the difficulties encountered by healthcare professionals when interacting with pregnant, labouring, and postpartum women. These data were conceptualised in light of existing literature, particularly in relation to the concept of epistemic injustice (Fricker, 2007) and its subsequent developments. From a theoretical perspective, the prevailing narrative surrounding pregnancy and childbirth was examined, focusing on its epistemological, phenomenological, and practical implications. Lastly, in collaboration with other researchers, a coding system was developed to identify instances of problematic communication along with episodes of epistemic and affective injustice within the healthcare context.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Margherita Ghiara
Supervisor: Carlo Martini
Abstract
This PhD project explores the issue of scientific disinformation, investigating available strategies to detect it, as well as the influence of political knowledge and of smartphone addiction on its detection. Using tools from cognitive sciences and social epistemology, it aims to understand how young adults navigate disinformation and develop strategies to combat it effectively.
Objectives
To obtain insights into scientific disinformation detection and factors influencing it amongst young adults. Results will be translated into useful recommendations for policy makers
Results achieved
Key achievements included the organisation and implementation of projects such as the MeetMe@School citizen science initiative and academic events such as the UniSR summer school, as well as the publication of the Disinformation In Schools report. Additional contributions were made through the co-supervision of a PPPA Masters student's dissertation project, which resulted in a pilot study on the perceived credibility of online news across generations and the role of aesthetic cues.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Cecilia Vergani
Supervisor: Roberto Mordacci
Abstract
The aim of this project is to contribute to an ethical reflection on AI that goes beyond providing technical solutions to techno-social problems. Focusing on the fact that technology is embedded in social relations and systems of production, the project aims to raise awareness of negative consequences in terms of power, exploitation, discrimination or injustice that arise from the development and use of AI in contemporary societies.
Objectives
The project aims to contribute to bridging the gap between the ethical reflection developed within industry and technological environments and the critical studies carried out in the philosophical-social sphere.
Results achieved
During the first year of research, the primary objective was to conduct an in-depth examination of the ethical discourse surrounding Artificial Intelligence. This entailed a systematic analysis of various AI-based technologies and systems currently
employed in contemporary societies, as well as the ethical and moral challenges associated with their implementation. Particular emphasis was placed on the philosophical methodologies and conceptual tools that can contribute to ethical
reflection in this domain. From a theoretical perspective, the study of authors within the tradition of Frankfurt School critical theory proved especially valuable in framing and addressing these issues.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 3.4: "Advanced university education and skills."
PhD Program: Cognitive and Behavioral Sciences
PhD student: Martina Lattanzi
Supervisor: Valentina Antonia Tobia
Abstract
A positive school climate promotes the academic performance and well-being of students and teachers. This project aims to investigate the impact of the different components of the school climate, with particular attention to educational and organizational innovations, the well-being and high-level cognitive skills of students and the well-being of teachers. The longitudinal study involves the administration of questionnaires, standardized tests and tasks
Objectives
The project will provide insights useful for the implementation of school policies aimed at improving the school climate and innovation.
Results achieved
The pilot study of the research project highlights that an increase in the perception of educational innovation is associated with greater school well-being, particularly in student-teacher and family-teacher relationships. Higher levels of innovation correlate with improved focus and a more positive school climate, characterized by better peer relationships, teacher support, and effective decision-making processes. The findings suggest that innovation plays a key role in enhancing well-being and the school climate.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Cognitive and Behavioral Sciences
PhD student: Laura Raffaelli
Supervisor: Francesco Benedetti
Abstract
Psychiatric research is increasingly focusing on eating disorders (EAD), exacerbated by a 20% rise in hospital admissions during the Covid-19 pandemic. Anorexia nervosa (AN), characterized by low caloric intake, low body weight, and distorted body image, shows significant brain structure and connectivity changes that partly normalize with weight restoration. Cognitive deficits appear to play a key role in exacerbating the AN symptomatology. Therefore, further research is needed to understand the role of neural correlates, inflammatory and metabolic markers in the development of cognitive deficit and the symptomatology of AN.
Objectives
The objectives are to examine brain, inflammatory, and metabolic changes in AN patients, their persistence after weight restoration, and how these factors contribute to the development of cognitive deficits in anorexia nervosa.
Results achieved
We collected 23 patients with anorexia nervosa and 15 healthy controls. All the patients perform an MRI scan, several neuropsychological and syntomatological tests, and a blood sample. I started to pre-process all the DTI and T1-weighted MRI images for performing TBSS, VBM and SBM analyses. Preliminary analyses suggest a negative association between several gray matter volumes (GMV) and self-reported cognitive deficits in patients with AN. However, any association was found between objective cognitive functions and GMV. Finally, resting-state images were pre-processed by using the CONN toolbox implemented in MatLab.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Cognitive and Behavioral Sciences
PhD student: Carla Blandino
Supervisor: Chiara Brombin
Abstract
Digital revolution has impacted not only the way people interact but also the relationship with the
self image. Advances in technology and increasing of AI power have significantly improved face
detection/recognition /editing algorithms. High accessibility of these editing tools associated with
reduced awareness in the use of digital technologies may have a significant psychological impact
especially on younger users in a developmental phase where they are already facing cruci al identity
construction process es.
Objectives
To improve theoretical psychological knowledge on how adolescents manage their digital self in online contexts, exploring the role of the social environment and psychological traits, and exploiting advanced data driven statistical techniques to test and generate new research hypotheses
Results achieved
Findings from Bayesian Network analysis on 1206 adolescents suggest that when adolescents perceive high social support, they show reduced preference for online interactions, improved school relationships, reduced internalizing symptoms and appearance anxiety, and higher self-concept clarity. Conversely, parental phubbing leads to school becoming a comfort zone, worsened psychological wellbeing in terms of internalizing symptoms and appearance anxiety, an increased preference for online interactions and use of social media for mood regulation.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Cognitive and Behavioral Sciences
PhD student: Andrea Salibba
Supervisor: Luigi Ferini Strambi
Abstract
The experimental hypothesis of the project is to produce a digital cognitive-behavioral treatment for chronic insomnia (dCBT-I) with an efficacy comparable to classical treatment, in a group modality. The digital modality would make it possible to reach more patients, offering greater accessibility and availability, for whom specific treatment is not available. These benefits, in the long run, could reduce the economic and social impact of insomnia in Italy.
Objectives
The overall objective of this research project is to produce a standardized protocol in the digital mode of CBT-I (dCBT-I) in the Italian language and evaluate its effectiveness.
Results achieved
We have conducted preliminary analyses on previously collected data to compare the effects of Cognitive Behavioral Therapy in both group and online formats (via communication software). The results show no significant differences in benefits between the two treatments. We are developing the tools for the P.h.D. project and digitalizing the treatment content. Additionally, we are preparing the documentation for the ethics committee.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Molecular Medicine
PhD Student: Alessia Bottoni
Supervisor:Roberto Furlan
Abstract
Neutrophils seem to be involved in autoimmune disease progression as effector of the innate immune system. Programmed cell death receptor 1 (PD-1) and its ligands are key inhibitors in immune response, attenuating signalling from the T cell antigen receptors. We identified a subpopulation of immunosuppressive neutrophils expressing PD-L2, providing new insights in the involvement of neutrophils role in neuroinflammation.
Objectives
To provide a full picture of the involvement of PD-L2+ neutrophils in the pathogenic mechanism of multiple sclerosis and provide a better knowledge of their biology.
Results achieved
From the bulk RNA sequencing results and the consequent ex vivo validation of them, we suggest the involvement of the interferon type I pathway (alpha and beta) in thesurface expression of PD-L2 from human neutrophils. We next evaluated it in MS subjects treated with interferon beta, with the aim to quantify the expression of PD-L2 on their neutrophils and to better investigate their involvement in the disease.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Molecular Medicine
PhD Student: Chiara Garsia
Supervisor: Angela Gritti
Abstract
We explore an approach in which human induced pluripotent stem cell (hiPSC)-derived NSCs (hiPSC-NSCs) are modified using state-of-the-art epigenome editing technology to empower their therapeutic plasticity, endowing them with an inducible anti-inflammatory/neuroprotective activity and myelinogenic potential, which will be assessed in relevant in vitro and in vivo models.
Objectives
The main goal of the project is to generate engineered hiPSC-NSCs with enhanced therapeutic plasticity, to study their biology and to evaluate their potential application as novel cell sources for the development of cell-based strategies for demyelinating disorders
Results achieved
We aim to enhance the pro-regenerative and myelinogenic potential of hiPSC-NSCs by overexpressing four therapeutic genes (TGs) using CRISPRa. We identified two transcription factors as the best TG combination for promoting oligodendrocyte differentiation of hiPSC-NSCs. Two TGs were selected to increase their pro-regenerative properties. We engineered hiPSC-NSCs to overexpress all four TGs and are testing their properties in vitro models.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
PhD Program: Molecular Medicine
PhD Student: Alexandra Maria Lazar
Supervisor: Arturo Chiti
Abstract
The project investigates the application of parametric imaging using long-axial field-of-view (LAFOV) PET/CT systems to improve oncological diagnostics. By providing detailed spatiotemporal data on radiotracer distribution, LAFOV PET/CT offers enhanced sensitivity and comprehensive whole-body imaging. The study aims to evaluate the technical feasibility, and clinical utility of this method for better understanding tumor physiology, improving diagnostic accuracy, and personalizing treatment strategies in oncology.
Objectives
To establish LAFOV PET-based parametric imaging as a reliable tool for tumor detection and characterization, and therapy response assessment, thereby enhancing personalized management of oncological patients.
Results achieved
During the first year of the project, we concentrated on optimizing reconstruction protocols for static PET imaging as a foundation for dynamic frame analysis. The aim was to enhance tumor visualization while minimizing the administered activity, ensuring reliable quantitative data. Our findings revealed that deep learning-based reconstructions significantly improved image quality, even under low-activity conditions, making them highly suitable for dynamic imaging applications. Building on this success, we are now applying these advanced methods to develop parametric imaging protocols tailored to neuro-oncological disorders. This work focuses on patients with gliomas undergoing FET PET/CT scans in our department, with the goal of advancing precision imaging and quantitative analysis in Oncology.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 3.4: "Advanced university education and skills."
PhD Program: Molecular Medicine
PhD Student:Miriam Meloni
Supervisor:Rossella Galli
Abstract
Glioblastoma (GBM) is the most common and deadliest brain tumor in adults. The average GBM patient’s survival time is 15 months and only 5% of patients survive more than five years. Recently, cancer metabolism emerged as an important opportunity both for treatment and diagnosis; this concept can be applied also to GBM. To this end, we subjected xenografts from intracranial injection of Glioma Stem Cell to untargeted metabolomics to identify metabolic vulnerabilities in the most aggressive mesenchymal (MES) subtype
Objectives
Harnessing metabolic dysregulation of MES subtype of GBM can reveal therapeutic targets to be exploited to improve treatment strategies and explore new diagnostic approaches
Results achieved
Through in vivo and in vitro analyses, we observed that the Kynurenine pathway (KP), the primary route for tryptophan metabolism, is specifically activated in the Mesenchymal (MES) GBM subtype, the one characterized by the highest immune infiltration. Although a few studies investigated KP regulation in GBMs, a deeper understanding of its role specifically in MES GBMs and in their tumor microenvironment is needed, as it may be instrumental for the clinical exploitation of KP inhibition in selected cohorts of GBM patients.
Project funded pursuant to Ministerial Decree No. 118 of March 2, 2023, within the framework of Investment 4.1: "Expansion of the number of PhD programs and innovative PhDs for public administration and cultural heritage."
DM n. 341
PhD Program: Molecular Medicine
PhD Student: Erika Di Domenico
Supervisor: Emilie Venereau
Abstract
HMGB1 is a nuclear protein released by cells upon stress or damage to act as a mediator of sterile inflammation and regeneration. A lower expression of HMGB1 within the cell, and its extracellular release have both been associated with hallmarks of aging. Our working hypothesis is that cells tend to release HMGB1 upon aging, due to constant cell stress and damage, leading to cell-intrinsic damage, as well as inappropriate inflammatory signalling and damage of cells/tissues. We will combine loss-of-function and gain-of-function experiments to decipher the contribution of HMGB1 in the aging process.
Objectives
We expect to decipher HMGB1’s contribution to the aging process, evaluating its value as biomarker to distinguish between healthy and pathological aging, and assessing the therapeutic potential of HMGB1 recombinant protein in aged cells.
Results achieved
Tumor-specific T cells have been enriched and expanded both from the blood and the lymph node of an esophageal adenocarcinoma complete responder patient. The analysis of the blood and the tumor draining lymph node of this patient highlighted a strong and shared T cell response against one or more of the predicted tumor neoantigens. Tumor neoepitope-specific T cell receptors were reconstructed by TCR sequencing and will be validated in vitro via functional assays.
Notice No. 341 of March 15, 2022, for the submission of proposals for the creation of “Extended partnerships between universities, research centers, and companies for the funding of basic research projects” – within the framework of the National Recovery and Resilience Plan, Investment 1.3, funded by the European Union – NextGenerationEU.
PhD Program: Molecular Medicine
PhD Student: Manuel Alejandro Montano Castillo
Supervisor: Marco Bacigaluppi
Abstract
Ischemic stroke has a worse clinical outcome in the elderly compared to young individuals. Age-related changes in the immune system may give rise to modified immune responses that could potentially impact the outcomes of strokes. We will investigate the age-related molecular and cellular changes of immune cells in elderly mice and their role in worsening ischemic stroke and identify new therapeutic targets.
Objectives
Identify molecular and cellular changes in the immune compartment that correlate with the outcome post-stroke to discover new therapeutic targets optimizing acute stroke treatment in the elderly.
Results achieved
We utilized physical training as a strategy to improve outcomes following experimental stroke in elderly mice and to study the differences between trained and sedentary groups. Our observations revealed that appropriate voluntary physical exercise leads to a better post-stroke outcome. In-depth analysis is needed to better understand the changes and the role of haematopoiesis, and of the inflammatory cells in the better stroke outcome.
Notice No. 341 of March 15, 2022, for the submission of proposals for the creation of “Extended partnerships between universities, research centers, and companies for the funding of basic research projects” – within the framework of the National Recovery and Resilience Plan, Investment 1.3, funded by the European Union – NextGenerationEU.
PhD Program: Molecular Medicine
PhD Student: Luisa Ricci
Supervisor: Simone Cardaci
Abstract
Cancer is considered an age-related disease. Interestingly, a hallmark of aging such as metabolic rewiring, is also instrumental in promoting malignant transformation. This project aims at understanding the molecular mechanisms driving metabolic reprogramming in cancer and determining how the metabolic landscape of the tumour microenvironment affects tumor progression.
Objectives
Using analytical chemistry, cell biology and computational approaches, we plan to identify immunometabolic features affecting tumor growth, as well as tumor-specific metabolic liabilities exploitable for clinical benefit
Results achieved
We investigated the metabolic reprogramming resulting from the loss of succinate dehydrogenase
(SDH) in cancer and demonstrated that SDH-deficient cells rely on mitochondrial alanine transaminase to sustain a favorable intracellular NAD+ pool, enabling glycolysis. This dependency renders SDH-deficient cells vulnerable to NAD+ depletion, achieved through pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway. Currently, we are exploring novel synthetic lethal metabolic vulnerabilities in SDHB-deficient cancer by integrating mathematical modeling with RNA-seq, proteomics, and nutrient exchange rate determined by LC-MS.
Notice No. 341 of March 15, 2022, for the submission of proposals for the creation of “Extended partnerships between universities, research centers, and companies for the funding of basic research projects” – within the framework of the National Recovery and Resilience Plan, Investment 1.3, funded by the European Union – NextGenerationEU.
PhD Program: Molecular Medicine
PhD Student: Ainhoa Viana Alzola
Supervisor: Dr. Jean-Michel Cioni
Abstract
Endosomes play essential roles in cellular function and survival by regulating multiple intracellular trafficking routes. Defects in endosomal trafficking have been shown to occur during healthy aging as well as a wide range of age-related human diseases, mainly affecting the nervous system. Proper endosomal trafficking is essential for neuronal function and survival. However, what causes the age-related impairments in endosomal functions in neurons, and the functional consequences, are not understood
Objectives
This project aims at investigating the link between impairments in endosomal trafficking and altered proteostasis in the aging brain by focusing on the molecular changes occurring on the organelle.
Results achieved
Our data confirmed age-related alterations in the endosomal pathway in the aged mouse brain, a phenotype recapitulated in our in vitro models. Additionally, we demonstrated that early endsosomes (EEs) harbor mRNAs in mature neurons,
suggesting that endosome-mRNA association persists at later stages. We have adapted protocols for isolating EEs from aged brains to analyze their transcriptome and we are developing models to study the relationship between age-related
endosomal trafficking impairments and mRNA localization dysregulation. Future experiments will focus on validating our findings and determining the mechanistic links between age-related endosomal defects and altered mRNA dynamics in
neurons.
Notice No. 341 of March 15, 2022, for the submission of proposals for the creation of “Extended partnerships between universities, research centers, and companies for the funding of basic research projects” – within the framework of the National Recovery and Resilience Plan, Investment 1.3, funded by the European Union – NextGenerationEU.
PhD Program: Molecular Medicine
PhD Student: Roberta Vacca
Supervisor: Raffaella Di Micco
Abstract
Hematopoietic Stem and Progenitor Cell (HSPC) gene therapies require an ex vivo activation step which, by mostly unexplored mechanisms, can strongly reduce HSPC fitness. It is emerging that an accelerated proliferation of HSCs, which is expected to occur during manipulation in culture but also upon transplantation, might lead to DNA damage through accumulation of oxidative stress, all factors implicated in HSC aging. Therefore, we propose to integrate knowledge of aged HSC biology to preserve HSC functionality during ex vivo culture and upon transplantation.
Objectives
The project aims at identifying the molecular and cellular mechanisms of physiological aging in HSCs and apply these findings to improve the efficacy of cell and gene therapy applications for the treatment of human diseases.
Results achieved
Our study revealed that gene editing triggers a premature aging phenotype in hematopoietic stem and progenitor cells (HSPCs) caused by the p38 MAPK-ROS axis in regulating cell cycle progression and DNA damage. We demonstrated that p38 inhibition enhances HSPC functionality and reconstitution capacity after transplantation without compromising gene editing efficiency. Additionally, we explored the effect of hypoxic conditions, which reduce oxidative stress but impair editing efficacy. Finally, studies in the context of HSC expansion showed that increased proliferation induces DNA damage and
reduces differentiation capacity, highlighting the importance of controlling proliferation to improve HSPC fitness.
Notice No. 341 of March 15, 2022, for the submission of proposals for the creation of “Extended partnerships between universities, research centers, and companies for the funding of basic research projects” – within the framework of the National Recovery and Resilience Plan, Investment 1.3, funded by the European Union – NextGenerationEU.
DM n. 351
PhD Program: Molecular Medicine
PhD Student: Francesca Rita Ogliari
Supervisor: Prof. Michele Reni
Abstract
Immunotherapy (IO) alone or in combination with chemotherapy (IO-CT) has become the standard of care for most patients with metastatic Non-Small Cell Lung Cancer (NSCLC). Nevertheless, 20 to 30% of patients do not benefit from these treatments facing a negative risk-benefit balance. An artificial intelligence (AI) platform, that can automatically extract patients’ data (clinical, pathological, radiological, laboratoristic) and analyse them, would help clinicians understand and highlight interconnected patterns and predictive algoritms of cancer-specific outcomes. Our study aims to train the AI tool in-clinic and validate it on a larger multicentric scale.
Objectives
Primary objective is precocely identify patients not responding to standard IO-based treatments; secondary objectives are severe toxicity and long-survivals prediction. Co-secondary endpoint is the feasibility of such approach (AI and its integration in data sources) in clinical research.
Results achieved
To date, the preliminary work conducted on the internal case series of HSR has allowed (i) the optimization of the interface between various hospital data sources and the data analysis platform, (ii) the testing of the feasibility of machine learning algorithms on tabular data derived from semi-automated data collection, (iii) the drafting of an internal workflow for the processing of DICOM images and the extraction of radiomic features potentially associated with tumor characteristics. These results will subsequently be validated on a multicenter scale within a network of approximately 18 hospitals on an international level
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Molecular Medicine
PhD Student: Nicolo Pecco
Supervisor: Andrea Falini
Abstract
Gliomas are a heterogeneous group of brain neoplasms and the search for biomarkers to characterize molecular status or predict prognosis could be a breakthrough advancement in neuro-oncology. This project aims at identifying reliable Magnetic Resonance Imaging (MRI) biomarkers for personalized profiling of brain gliomas. An Artificial Intelligence (AI) model based on Deep Learning (DL) using transfer learning will be developed for glioma identification on retrospective conventional and advanced MRI datasets, followed by a radiomic analysis to extract relevant quantitative features linked to pathological, molecular and other clinical outcomes. DL models will be tested on a prospective cohort of glioma patients and on open-source databases (e.g., TCIA/TGCA-GBM), for external validation purposes.
Results achieved
'We explored glioma segmentation using different DL architectures for a brain extraction tasks. Results were pubblished in Radiology Artificial Intelligence journal (https://doi.org/10.1148/ryai.230229). In the second year, the Swin-UNETR and nnU-NET were evaluated and compared across Eedema, enhancment and Necrosis compartments and with different radiologists. The edema was the most easily identifiable region, while Swin-UNETR showed a tendency to detect more necrotic regions compared to radiologists. NN-UNET showed superior performance in edema segmentation, consistency across different radiologists, and competitive results in T1-enhanced tissue analysis
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Martina Giovine
Supervisor: Bianca Cepollaro
Abstract
This project concerns non-discriminatory language and its implementability within public administrations, taking on challenges such as defying inclusive language, providing a survey of the main existing proposals, trying to develop a model for assessing and evaluating them, surveying and interpreting the existing empirical studies on the topic, investigating the relationship between communication, stereotypes, and biases, assessing the existing policies and good practices.
Objectives
The aim of the project is to make an original contribution to the scientific debate and to participate in the governance, organisation and strategic direction of public administrations.
Results achieved
Analysis of the institutional and administrative landscape concerning the topic of implementing guidelines for gender-inclusive communication; drafting guidelines for the Vita-Salute San Raffaele University; understanding the relationship between gender, stereotypes and language and developing a reflection on which linguistic practices are most useful in countering gender stereotypes
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Edoardo La Ragione
Supervisor: Andrea Tagliapietra
Abstract
The project intends to investigate the paradigm shifts that have occurred following the entry of the "digital space" into governance practices and the forms of life it has opened up. In particular, it is necessary to think about how the space of the 'political' is being redefined today where certain traditional criteria of definition seem to no longer hold sway.
Objectives
We are expected to be able to adequately 'map' the present, reconstructing its past genealogically and trying to see possible future outcomes.
Results achieved
In collaboration with the Scuola Nazionale dell'Amministrazione (SNA) in Rome, the research focused on the topic of international standard setting as a governance practice aimed at quantifying and evaluating the performance of public
administration in line with the developments of New Public Management and to study its applications in the field. The research critically investigates its theoretical assumptions and practical implications
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Cognitive and Behavioral Sciences
PhD student: Francesca Berra
Supervisor: Andrea Galbiati
Abstract
Insomnia is characterized by difficulty initiating or maintaining sleep and resulting in daytime impairment. The hyperarousal model suggests that it is perpetuated by physiological and cognitive arousal that is influenced by stress. So sleep reactivity (SR), the degree to which stress disrupts the sleep system, is a critical concept in understanding insomnia. When SR exceeds a certain threshold, it can lead to sleep disorders. The AIE model highlights attention's role in insomnia, and understanding attentional shifting strategies could aid in managing SR.
Objectives
Investigate the relationship between insomnia and sleep reactivity manipulating it to evaluate the impact on subjects with and without insomnia symptoms, with a focus on REM sleep, and exploring the role of attention.
Results achieved
We developed, tested, and validated a tool capable of inducing stress, which has proven effective in eliciting sleep disturbances in the tested subjects. The mediating role of the attentional domain in this relationship has yet to be verified
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD Student: Giulio Pennacchioni
Supervisor: Francesca Pongiglione
Abstract
The latest IPCC reports confirm the anthropogenic origin of climate change, while adequate political actions are still lacking. Despite the consensus among moral philosophers about the importance of individual action, participation in climate mitigation is still limited. The same holds true for the collective action of institutions, whose responsibility also extends to communication and education about climate change.
Objectives:
The objective is to define the moral and epistemic responsibilities of individuals and institutions and to promote broader engagement against climate change.
Results achieved
The achieved results highlight how the implementation of sustainable education, not confined to a purely technical dimension, can foster greater awareness and participation. This integrated approach combines moral and epistemic responsibilities, enabling individuals and institutions to become more active agents in mitigating and adapting to the climate crisis. The challenge, therefore, lies in strengthening the understanding of sustainability as a complex solution, capable of driving both individual and collective actions. Transformative education, rooted in sustainability and encompassing both formal and informal learning contexts, emerges as an essential element to overcome the current inaction.
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 3.4 - "Advanced university teaching and skills".
PhD Program: Cognitive and Behavioral Sciences
PhD student: Alessandra Castelnuovo
Supervisor: Maria Salsone
Abstract
Obstructive Sleep Apnea Syndrome (OSAS) is a sleep related breathing disorder, characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to sleep fragmentation. OSAS has a high epidemiological impact (9-38% of general population), it is frequently reported in male and increasing with the age. Interestingly, there is evidence for a strict correlation between OSAS and neurodegenerative disorders, such as Alzheimer’s Dementia. CPAP treatment could revert OSAS related-cognitive impairment.
Objectives
The aim of this project is to create a web-based platform, to collect the clinical-instrumental data in order to identify OSAS profiles at high risk for neurodegeneration and predict the efficacy to CPAP treatment.
Results achieved
Data show an average sample age of approximately 60 years, with a higher prevalence in males. About half of the sample has a medical history of arterial hypertension and cardiovascular disorders. Most patients have undergone a neuropsychological assessment, which reveals lower scores compared to individuals of the same sex and age in the domains of memory and executive functions. Follow-up data are currently being collected.
By Ministerial Decree No. 351 of April 9, 2022, the Ministry of Universities and Research Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
PhD Program: Philosophy
PhD student : Chiara Borgonovo
Supervisor: Francesca Pola
Abstract
The research project adopts an interdisciplinary approach, integrating modern image theories and art history, to examine the material aspects of digital media in relation to artworks that incorporate technological components. It analyzes the complex challenges posed by such works at the interpretive, conservation, and curatorial levels, while tracing the historical development of media art in Italy, identifying relevant case studies, and evaluating the historical-critical, conservation, and curatorial strategies applied or applicable in such contexts.
Objectives
The main goal of the project is to identify new methodological approaches and collaborative strategies applied nationally and internationally for studying, preserving and curating media art. The project aims to generate insights that will promote knowledge advancement and help establish best practices in media art research, conservation, and curatorship within Italy.
Results achieved
The project enabled the reconstruction of a state-of-the-art overview, updated in light of developments in contemporary debates. A six-month research period was conducted at the Studio Azzurro archive, where selected case studies were explored in depth, supporting the design of a relational database.
Additionally, a mapping of the Italian institutional landscape was carried out through a campaign of interviews and a series of meetings with industry professionals at the international level. The research led to the development of innovative models for the preservation, presentation and archiving of media art, with a particular focus on the Italian context.
By Ministerial Decree No. 351 of April 9, 2022, Investment 4.1 – "Extension of the number of PhDs and innovative PhDs for public administration and cultural heritage."
DM n. 352
PhD Program: Molecular Medicine
PhD Student: Alessandra Weber
Supervisor: Luigi Naldini
Abstract
Editing by homology direct repair (HDR) in human HSPCs remains poorly efficient and this limits its therapeutic applications in most diseases. Novel strategies enabling enrichment of HDR-edited HSPCs would decrease competition by unedited cells, improving therapeutic efficacy and at the same time increasing safety by purging out cells harboring undesired loss of-function editing outcomes at the target site.
The aim of this PhD project is to develop innovative strategies for ex-vivo and in-vivo enrichment of human edited HSPCs harboring targeted integration of highly expressed cassettes into genomic safe harbors (GSHs).
Objectives
Selection strategies can be achieved by i) ex-vivo sorting of engineered cells by means of editing-coupled selector, or ii) conferring in-vivo selective disadvantage to cells not undergoing HDR.
Results achieved
As for the identification of new potential genomic safe harbors, we thought that lentiviral vector common integration sites might be interesting candidates since they ensure robust expression of the transgene over time and they are not associated with carcinogenesis in clinical trials and experimental models. As for the in vivo counterselection of HSPCS’ undesired edits, we identified three different loci in which we demonstrated a spontaneous purge out of indels and the persistence of HDR-edited cells only in the long-term graft.
By Ministerial Decree No. 352 of April 9, 2022, within the framework of Investment 3.3: "Introduction of innovative PhD programs addressing the innovation needs of companies and promoting the employment of researchers by enterprises."
DM n. 630
PhD Program: Molecular Medicine
PhD Student: Ceriotti Selene
Supervisor: Stefania Crippa
Abstract
Mucopolysaccharidoses (MPS) are a group of rare genetic lysosomal storage disorders (LSDs) caused by enzyme deficiencies. MPS IV (or Morquio syndrome) includes two subtypes: MPS IVA (GALNS) and MPS IVB (GLB1), both characterized by severe skeletal abnormalities that current therapies fail to correct. For this reason, this project is focused on the development of novel gene therapy approaches to treat MPS IVA and MPS IVB based on previous preclinical and clinical data showing the superior efficacy of gene therapy compared to standard treatments in other forms of LSDs.
Objectives
The project aims to test the safety and efficacy of gene therapy in preclinical animal models of MPS IVA and MPS IVB, and using clinically relevant in vitro models generated from patient-derived induced pluripotent stem cells.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Collura Nicoletta
Supervisor: Andrea Domenico Menegon
Abstract
Glioblastoma Multiforme (GBM) is a highly aggressive brain tumor showing therapy-resistance due to the presence of cancer stem cells (CSCs). CSCs specifically express the acid sensing ion channel (ASIC) isoform 3 as a potential adaptation to the tumor acidic niche. Pharmacological activation of ASIC3 selectively damages CSCs without harming neurons thus representing a promising new therapeutic strategy for GBM treatment.
Objectives
The study aims at investigating the role of ASIC3 in glioblastoma stem cells physiology using in vitro and in vivo models as well as its potential as therapeutic pharmacological target.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Dall’Ara Chiara
Supervisor: Marina Macchini
Abstract
Pancreatic adenocarcinoma is a lethal disease for which current therapeutic options are limited, and the research for innovative treatments is crucial to improve patient survival. Antibody-drug conjugates are anticancer agents that combine the selectivity of monoclonal antibodies with the cytotoxicity of chemotherapeutic drugs. In this project, we aim to investigate the efficacy of this new class of drugs in preclinical models of pancreatic adenocarcinoma, focusing on specific and rationally designed drug combinations.
Objectives
Given their strong antitumor activity, we hypothesize that antibody-drug conjugates alone or in combination with chemotherapy or targeted therapies could represent a new therapeutic option for pancreatic adenocarcinoma patients.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Di Coste Alessia
Supervisor: Massimo Alfano
Abstract
Bacillus Calmette-Guérin (BCG) is the standard treatment for high-grade non–muscle-invasive bladder cancer, but it can cause side effects and only works for about half of the patients. Recent studies suggest that the microbiota may predict response to BCG treatment. This prospective observational study aims to identify a specific microbiota signature that can early detect patients who are likely to respond to BCG. A targeted approach could improve quality of life and reduce high healthcare costs associated with this type of cancer.
Objectives
The primary objective of this project is to identify the microbial profile found in urine and/or feces that could help clinicians choose the best candidates for BCG treatment in the future, making therapies more effective.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Lauri Gaetano
Supervisor: Paolo Giorgio Arcidiacono
Abstract
This project integrates endoscopic ultrasound (EUS) with artificial intelligence to improve diagnosis, staging, and prognosis of pancreatic cancer. EUS videos and biological samples will be collected from patients with pancreatic lesions to train predictive models capable of distinguishing pancreatic cancer, forecasting chemotherapy response, and identifying molecular alterations.
Objectives
To enhance early diagnosis and prognostic prediction in pancreatic cancer by integrating clinical, EUS imaging, and molecular data using deep learning models.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Morozumi Tetsu
Supervisor: Maria Assunta Rocca
Abstract
Motor rehabilitation plays a key role in improving quality of life in patients with multiple sclerosis. Approaches such as action observation therapy and aerobic exercise have shown promising benefits, but the underlying mechanisms have not yet been fully understood. Moreover, individual responses to these rehabilitative strategies may vary due to patient heterogeneity. Advanced MRI techniques may help to identify potential markers of specific motor functions, as well as MRI correlates of clinical improvement following different rehabilitative strategies and predictors of treatment response.
Objectives
Using structural and functional MRI, this project aims to provide a comprehensive characterization of the MRI substrates of different motor abilities, to explore central nervous system modifications induced by different rehabilitative strategies and identify reliable predictors of response to these interventions in multiple sclerosis patients.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Molecular Medicine
PhD Student: Patrone Margherita
Supervisor: Emilie Venereau
Abstract
HMGB1 is a nuclear protein involved in tissue damage response, playing key roles in both inflammation and regeneration. Under oxidative stress, such as in Duchenne muscular dystrophy, HMGB1 becomes oxidized, exacerbating inflammation. Therefore we have developed an engineered variant (3S), oxidation-resistant, that promotes muscle regeneration in preclinical models. Recent data also suggest that HMGB1 recycling within muscle fibers may play a role during regeneration, opening new perspectives on its mechanism of action.
Objectives
This project aims to evaluate the therapeutic potential of the 3S variant and to investigate the mechanisms regulating its activity, with the goal of developing new regenerative strategies, particularly for muscular dystrophies.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
PhD Program: Philosophy
PhD Student: Bigliardi Nicola
Supervisor: Francesco Valagussa and Antonio
Nizzoli
Abstract
This research investigates the representation of the human face within
contemporary artistic, cultural, and technological contexts. It explores make-up not only as
a cosmetic practice, but as a broader concept encompassing the techniques, technologies,
and perceptions that shape facial identity. In an era of continuous transformation of beauty
ideals and self-image, questioning these dynamics becomes essential. Art plays a crucial
cognitive role in defining and redefining aesthetic canons. The project offers a
comprehensive reflection on current challenges and shifts related to the face.
Objectives
This research aims to explore how new technologies influence society,
focusing on interpersonal dynamics, self-image, and individual-world interactions.
Through this analysis, the project seeks to develop methodologies for studying self-image
in motion and to understand the broader implications across various social fields.
Ministerial Decree No. 630 of 24 April 2024, within the framework of Investment 3.3 “Introduction of innovative doctoral programs that respond to the innovation needs of companies and promote the recruitment of researchers by enterprises.”
DM n. 630
PhD Program: Philosophy
PhD Student: Calzetta Daniele
Supervisor: Vito Limone
Abstract
This project aims to offer an in-depth and up-to-date analysis of the Vatican administrative system in comparison with the Italian administrative system, examining not only the historical evolution and peculiarities of the Holy See, but also the transformations which have taken place both structurally and in the interactions between the two States from the perspective and thanks to the actions of Pope Paul VI.
Objectives
- Understand how, and above all whether, Paul VI’s convictions were translated into pastoral and administrative action
- To understand the evolution of the Holy See in terms of its structures and its relationship with the Italian state, as seen through the eyes of a privileged witness who held key positions at the intersection of priestly ministry and political activity: ecclesiastical assistant to the FUCI, Substitute and Pro-Secretary of the Secretariat of State, Archbishop of Milan and, finally, Pope
Ministerial Decree No. 629 of 24 April 2024, within the framework of Investment 4.1 “Expansion of the number of PhD programs and innovative doctorates for the public administration and cultural heritage.”