San Raffaele Open Research Data Repository
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Neutrophil to lymphocyte ratio and antidepressant treatment response in patients with major depressive disorder: Effect of sex and hippocampal volume
No full textSeveral factors may affect response to treatment in Major Depressive Disorder (MDD) including immune/inflammatory alterations and regional brain volumes, particularly in hippocampal regions which have shown to be influenced by inflammatory status. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker found to be elevated in depressed women in large population studies. Here we investigate the effect of NLR on treatment response in MDD patients, and the role of sex and hippocampal volume on influencing this relationship. A sample of 124 MDD depressed inpatients (F = 80) underwent MRI acquisition, admission NLR was calculated by dividing absolute neutrophil by absolute lymphocyte counts and depression severity was assessed at admission and discharge via the Hamilton Depression Rating Scale (HDRS). As a measure of treatment response, delta HDRS was calculated. We found a significant moderation effect of sex on the relationship between NLR and Delta HDRS: a negative relation was found in females and a positive one in males. NLR was found to negatively affect hippocampal volumes in females. Both left and right hippocampal volume positively associated with Delta HDRS. Finally, left hippocampal volume mediated the effect of NLR on Delta HDRS in females. Sex moderated the relation between inflammation and treatment response in line with previous reports linking inflammation to hampered antidepressant effect in females. Further, this effect is partially mediated by hippocampal volume, suggesting that antidepressant response may be hampered by the detrimental effect of inflammation on the brain
Multimodal brain-derived subtypes of Major depressive disorder unveil multivariate associations between anergic symptoms, childhood trauma, immune-inflammatory markers and treatment-resistance
No full textAn estimated 30% of Major Depressive Disorder (MDD) patients exhibit resistance to conventional antidepressant treatments. Identifying reliable biomarkers of treatment-resistant depression (TRD) represents a major goal of precision psychiatry, which is hampered by the clinical and biological heterogeneity underlying MDD. To parse heterogeneity and uncover biologically-driven subtypes of MDD, we applied an unsupervised data-driven framework to stratify 102 MDD patients on their neuroimaging signature, including extracted measures of cortical thickness, grey matter volumes, and white matter fractional anisotropy. Our novel analytical pipeline integrated different machine learning algorithms to harmonize neuroimaging data, perform data dimensionality reduction, and provide a stability-based relative clustering validation. The obtained clusters were then characterized for immune-inflammatory peripheral biomarkers, TRD, history of childhood trauma and different profiles of depressive symptoms. Our results indicated two different clusters of patients, differentiable with 67% of accuracy: 1) one cluster (n=59) was associated with a higher proportion of TRD compared to the other, and higher scores of energy-related depressive symptoms, history of childhood abuse and emotional neglect; this cluster showed a widespread reduction in cortical thickness (d=0.43-1.80) and volumes (d=0.45-1.05), along with fractional anisotropy in the right superior fronto-occipital fasciculus, stria terminalis, and corpus callosum (d=0.46-0.52); 2) the second cluster (n=43) was associated with cognitive and affective depressive symptoms and thicker cortices and wider volumes compared to the other. Multivariate analyses revealed distinct brain-inflammation relationships between the two clusters, with increase in pro-inflammatory cytokines and chemokines being associated with decreased cortical thickness and grey matter volumes. Our stratification of MDD patients based on structural neuroimaging identified clinically-relevant subgroups of MDD with specific symptomatic, childhood trauma, and immune-inflammatory profiles, which can contribute to the development of tailored personalized interventions for MDD.
For any clarification, please contact the corresponding author (Dr. Federica Colombo) at [email protected]
Potential phosphorylation of Liprin-α1 at threonine 701 regulates integrin-mediated cell motility (PONE-D-25-29015_R2)
No full textA dynamic protein network at the leading edge of motile cells is needed to coordinate events required for efficient cell motility. Previous work has shown that the Ser/Thr kinase DYRK3 affects the assembly of this network, and phosphorylates its component Liprin-α1, a scaffold protein regulating adhesion turnover and cell motility. We have looked for phospho-sites of Liprin-α1 relevant for the regulation of cell motility, by examining the role played by serine/threonine residues phosphorylated within the intrinsically disordered regions of Liprin-α1. Phospho-null mutations within either the amino-terminal or the carboxy-terminal disordered regions affect Liprin-α1 phosphorylation induced by DYRK3. Functional analysis shows that mutations within the amino-terminal region do not affect cell motility, while a set of carboxy-terminal mutations reduces the positive effects of Liprin-α1 on cell spreading on the extracellular matrix. Among several candidate phospho-sites in this protein region, we identify Thr701 as one of the potential main targets of DYRK3 activity in Liprin-1. The phospho-null mutation of Thr701 specifically inhibits Liprin-1–induced potentiation of cell spreading on fibronectin. Our findings contribute to highlight the complexity of the regulation of Liprin-αprotein functions by phosphorylation/dephosphorylation events. Given the involvement of Liprin-α proteins in tumor cell motility and invasion, in-depth understanding of this regulatory complexity may highlight new possibilities for therapeutic intervention
Aerobic capacity moderates the association between cervical cord atrophy and clinical disability in mildly disabled multiple sclerosis patients
No full textSpinal cord atrophy is a key contributor to disability in multiple sclerosis (MS), with early and progressive loss of cervical cord volume correlating with worsening clinical outcomes. This study explored whether aerobic capacity moderates the association between spinal cord atrophy and clinical disability in people with MS. A cross-sectional analysis was conducted on 51 MS patients with mild to moderate disability (Expanded Disability Status Scale [EDSS] ≤ 6.0) and 33 age- and sex-matched healthy controls (HCs). All participants underwent 3T brain MRI to assess normalized mean upper cervical cord area (nMUCCA), a surrogate for spinal cord atrophy. Aerobic capacity was assessed via peak oxygen consumption (VO₂peak) measured during cardiopulmonary exercise testing (CPET), with low aerobic capacity defined as a z-score < –1.64.
MS patients demonstrated significantly reduced nMUCCA and VO₂peak compared to HCs. Within the MS cohort, 61% were classified as having low aerobic capacity. Although no major differences in brain volumes or clinical characteristics (aside from body mass index) were observed between low and high aerobic capacity subgroups, a significant negative correlation between nMUCCA and EDSS was found only in those with low aerobic capacity. Moderation analysis confirmed a significant interaction between spinal cord atrophy and aerobic capacity in predicting disability (β = –0.099, p = 0.012). Specifically, reduced nMUCCA was associated with higher disability only in MS patients with low aerobic capacity, but not in those with high aerobic capacity.
These findings suggest that greater aerobic capacity may attenuate the detrimental impact of spinal cord atrophy on clinical disability in MS, acting as a physical reserve factor. This highlights the potential of aerobic fitness enhancement as a non-pharmacological strategy to buffer neurodegenerative effects and support functional outcomes in MS, especially in the early stages of the disease
Influence of cardiorespiratory fitness and MRI measures of neuroinflammation on hippocampal volume in multiple sclerosis
No full textThis study investigated the impact of neuroinflammation and cardiorespiratory fitness (CRF) on hippocampal volume in patients with multiple sclerosis (MS), with a focus on differences between clinical phenotypes. A total of 81 MS patients were included, of whom 27 had relapsing–remitting MS (RRMS) and 54 had progressive MS (PMS). An additional 45 age- and sex-matched healthy controls were enrolled for structural brain imaging comparisons. All participants underwent high-resolution 3T MRI to assess normalized brain, gray matter, hippocampal, and thalamic volumes. In MS patients, aerobic capacity was assessed via maximum oxygen consumption (VO₂max) using cardiopulmonary exercise testing, while T2-hyperintense lesion volume (T2-LV) and choroid plexus volume (CPV) were quantified as MRI markers of neuroinflammation.
Compared to healthy controls, both RRMS and PMS patients exhibited significantly lower brain and regional volumes, including the hippocampus, and higher T2-LV and CPV, reflecting increased neuroinflammation. Regression analyses revealed that T2-LV and CPV were the most influential predictors of global and regional brain atrophy in both MS phenotypes. Notably, VO₂max was identified as a significant predictor of hippocampal volume only in RRMS patients, explaining 16.9% of the variance and retained as a relevant predictor alongside T2-LV in multivariate models. In contrast, VO₂max had no significant explanatory value for hippocampal or other volumetric outcomes in PMS patients.
These findings suggest a selective and clinically relevant association between aerobic fitness and hippocampal integrity in the early, relapsing phase of MS, possibly mediated by mechanisms such as neurogenesis or neuroprotection. In more advanced stages of the disease, such as PMS, widespread neurodegeneration may overshadow the potential benefits of aerobic capacity. The results underscore the importance of promoting CRF early in the disease course as a strategy to preserve hippocampal structure and potentially mitigate cognitive decline
"Chimeric enzymes enhance treatment potential for globoid cell leukodystrophy through hematopoietic stem cell gene therapy" and GR 2019-12369357 (final report)
No full text"Chimeric enzymes enhance treatment potential for globoid cell leukodystrophy through hematopoietic stem cell gene therapy" - PMID: 40988335 - DOI: 10.1016/j.ymthe.2025.09.030
Globoid cell leukodystrophy (GLD) is a fatal lysosomal storage disorder caused by a deficiency in the β-galactosylceramidase (GALC) enzyme, leading to severe demyelination and neurodegeneration, and often death before the age of 2 years. Hematopoietic stem/progenitor cell transplantation (HSPC-T) has limited efficacy due to inadequate GALC delivery to the central (CNS) and peripheral nervous systems (PNS) and associated risks. In vivo gene therapy (GT) using adeno-associated viral vectors shows promise, but safety concerns persist. This research presents a strategy using lentiviral (LV) vector-mediated ex vivo HSPC-GT with a chimeric GALC enzyme that incorporates peptides from α-L-iduronidase (IDUA) and apolipoprotein E II (APO) to enhance expression and blood-brain barrier penetration. The chimeric IDUAsp.GALC.APO enzyme exhibited superior production and secretion compared to native GALC and previous chimeric variants in LV-transduced HSPCs, resulting in improved cross-correction and normalization of GALC activity in GLD neural cells. Proof-of-concept studies demonstrated effective enzyme production, secretion, and cross-correction capability of macrophages from GLD patients. In vivo results showed stable gene marking, sustained enzyme production, and efficient delivery of the chimeric GALC in affected organs, including the CNS and PNS. These findings highlight the potential of HSPC-GT using chimeric GALC enzymes as an innovative therapeutic approach for treating GLD. Data related to the paper are available in the folder with the same name.
"Enhancement of expression, bioavailability and cross-correction of chimeric GALC enzyme to refine gene therapy approaches for globoid cell leukodystrophy" - GR 2019-12369357 - Final Report
In this project, we propose a lentiviral vector-mediated gene therapy with a chimeric GALC enzyme engineered for improved expression and blood-brain barrier penetration as therapeutic approach for GLD. Our findings demonstrate that the chimeric enzyme, when expressed in LV-transduced human HSPCs and GLD iPSC derived NPC progeny, exhibits enhanced production and secretion compared to native GALC and prior chimeric variants. This leads to significant cross-correction of GALC activity in GLD neural cells. In vivo studies in immunodeficient mice and a severe GLD mouse model confirmed stable gene marking and sustained enzyme production, emphasizing our strategy's potential for effective therapeutic delivery and cross-correction of affected tissues. The data related to the final report of GR 2019-12369357 are available in the folder with the same name
Disentangling the Genetic Landscape of Peripartum Depression: A Multi-Polygenic Machine Learning Approach on an Italian Sample
No full textUsing a multi-polygenic score approach, we characterized the relationship between genome-wide information and the history of PPD in patients with mood disorders, with the hypothesis that multiple polygenic risk scores (PRSs) could potentially influence the development of PPD. The PLS linear regression in the whole sample defined a model explaining 27.12% of the variance in the presence of PPD history, 56.73% of variance among MDD, and 42.96% of variance in BD. Our findings highlight that multiple genetic factors related to circadian rhythms, inflammation, and psychiatric diagnoses are top contributors to the prediction of PPD. Specifically, in MDD, the top contributing PRS was monocyte count, while in BD, it was chronotype, with PRSs for inflammation and psychiatric diagnoses significantly contributing to both groups
Dataset "Progetti ordinari di Ricerca Finalizzata", RF-2019-12368847
No full textData generated under the umbrella of the research grant “RF-2019-12368847” have been included in the pubblication "Specific types of male infertility are correlated with T cell exhaustion or senescence signatures" (https://doi.org/10.1038/s41467-025-56193-2).
Below are the links to the open-access data repository where the data have been published.
The first link to GEO Repository contains all the data generated by single cell RNA sequencing
The second link to the San Raffaele Open Research Data Repository contains all the other data generated and used to build manuscript figures
Unravelling Plasma Extracellular Vesicle Diversity With Optimised Spectral Flow Cytometry
No full textExtracellular vesicles (EVs) are crucial for intercellular communication and are found in various biological fluids. The identification and immunophenotyping of such small particles continue to pose significant challenges. Here, we have developed a workflow for the optimisation of a next-generation panel for in-depth immunophenotyping of circulating plasma EVs using spectral flow cytometry. Our data collection followed a multistep optimisation phase for both instrument setup and 21-colour panel design, thus maximising fluorescent signal recovery. This spectral approach enabled the identification of novel EV subpopulations. Indeed, besides common EVs released by erythrocytes, platelets, leukocytes and endothelial cells, we observed rare and poorly known EV subsets carrying antigens related to cell activation or exhaustion. Notably, the unsupervised data analysis of major EV subsets revealed subpopulations expressing up to five surface antigens simultaneously. However, the majority of EVs expressed only a single surface antigen, suggesting they may not fully represent the phenotype of their parent cells. This is likely due to the small surface area or the biogenesis of EVs rather than antibody steric hindrance. Finally, we tested our workflow by analysing the plasma EV landscape in a cohort of systemic lupus erythematosus (SLE) patients. Interestingly, we observed a significant increase in CD54+ EVs, supporting the notion of elevated circulating ICAM under SLE conditions. To our knowledge, these are the first data highlighting the importance of a spectral flow cytometry approach in deciphering the heterogeneity of plasma EVs paving the way for the routine use of a high-dimensional immunophenotyping in EV research
Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth
No full textThese files contain the raw images and dataset used to generate Figures 1A, 5 (panels B, C, and G), 6 (panels A, D, E and F), and S3A of the article titled “Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth” by A.M. Gasparri, A. Pocaterra, B. Colombo, G. Taiè, C. Gnasso, A. Gori, F. Pozzi, A. Smith, F. Magni, A. Ugolini, M. Doglio, M.C. Bonini, A. Mondino, A. Corti, and C. Curnis, published in J Exp Clin Cancer Res 44, 88 (2025). https://doi.org/10.1186/s13046-025-03352-4
The research leading to these findings was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) under IG 2019 – ID. 23470 project – P.I. Angelo Corti; Fondazione AIRC 5 per Mille 2019 program (ID. 22737), P.I. MC Bonini, Group Leader A. Corti and A. Mondino; collectively supported by the national funding organizations under the framework of the ERA-NET TRANSCAN-3 initiative (ReachGlio project, ID: TRANSCAN2022-784-017 – Italian Ministry of Health ID: ERP-2022-23683648 to F. Curnis); and National Recovery and Resilience Plan (NRRP), M6/C2_CALL 2023 (project: POC-2023-12377318 to F. Curnis) funded by the European Union – NextGenerationEU