IRIS UniSR (’Università Vita-Salute San Raffaele)
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La filosofia di Lucio Battisti
No full textRilettura del percorso creativo di Lucio Battisti attraverso la categoria di de-costruzion
Approcci tollerogenici per prevenire le risposte immunitarie indesiderate nelle terapie di sostituzione proteica e genica per le malattie da accumulo lisosomiale
No full textLe malattie da accumulo lisosomiale (LSD) sono condizioni genetiche rare causate da mutazioni nei geni che codificano per gli enzimi lisosomiali, portando all'accumulo sistemico di metaboliti non degradati. Le attuali strategie terapeutiche includono la terapia di sostituzione enzimatica (ERT), il trapianto di cellule staminali ematopoietiche e la terapia genica. L'ERT rimane il trattamento standard per molte LSD, consistendo nell'infusione periodica di enzimi umani ricombinanti per fornire ai pazienti una fonte funzionale di enzimi. Nonostante i benefici, le risposte immunitarie contro questi enzimi ricombinanti possono ostacolare l'efficacia della terapia. Di conseguenza, le strategie di induzione della tolleranza immunitaria (ITI) sono diventate metodi essenziali e spesso efficaci per gestire le risposte immunitarie associate all'ERT. Le cellule dendritiche tollerogene (tolDC) svolgono un ruolo critico nel promuovere la tolleranza specifica per l'antigene (Ag) e hanno mostrato promesse nel modulare le risposte immunitarie in condizioni mediate dalle cellule T CD4+. Abbiamo stabilito un protocollo per generare tolDC attraverso la trasduzione con un vettore lentivirale che codifica per IL-10 e un antigene specifico fuso alla catena invariante (Ii). Questo approccio garantisce una presentazione stabile dell'antigene codificato sia nel contesto MHC di classe I che di classe II, facilitando il riconoscimento da parte delle cellule T CD4+ e CD8+. La nostra ricerca mira a sviluppare una strategia basata su tolDC specifica per l'antigene per affrontare le risposte immunitarie avverse, che potrebbe servire come immunoterapia adiuvante per i pazienti trattati con ERT. Per raggiungere questo obiettivo, abbiamo analizzato la risposta immunitaria specifica per l'enzima e lo stato immunitario generale dei pazienti con LSD che ricevono ERT (mucopolisaccaridosi di tipo IVA, malattia di Pompe e alfa-mannosidasi). I nostri risultati indicano che il sangue periferico (PB) dei pazienti con LSD trattati con ERT è arricchito di citochine e chemochine pro-infiammatorie. Questo profilo infiammatorio è riflesso nel compartimento cellulare, dove abbiamo osservato una proporzione aumentata di neutrofili e monociti attivati rispetto ai controlli sani (HC). Nonostante questo fenotipo attivato, i monociti dei pazienti con LSD trattati con ERT possono differenziarsi in DC-10 funzionali. Inoltre, abbiamo notato una proporzione elevata di cellule T follicolari helper (Tfh) e cellule B produttrici di anticorpi rispetto ai controlli sani. Di conseguenza, sono stati rilevati livelli variabili di anticorpi anti-enzima nei sieri di diversi pazienti; tuttavia, non siamo stati in grado di identificare una risposta cellulare T specifica per l'enzima nel loro PB. Per chiarire i meccanismi sottostanti all'induzione degli anticorpi anti-enzima, abbiamo valutato la fattibilità dell'approccio DCIL-10/Ag in un modello murino di MPS-I (IDUA-/-). Abbiamo stabilito un protocollo ERT che replica la risposta immunitaria osservata nei pazienti umani e determinato che la produzione di anticorpi dipende dalle cellule T CD4+. Notabilmente, le risposte cellulari T specifiche per l'enzima sono state rilevate solo all'inizio del trattamento ERT. Abbiamo generato cellule dendritiche derivate dal midollo osseo (DCIL-10/IDUA) e validato la loro capacità di modulare la risposta cellulare T CD4+ anti-IDUA in vitro. Inoltre, quando le DCIL-10/IDUA sono state somministrate all'inizio del trattamento ERT, hanno modulato efficacemente la risposta cellulare B anti-IDUA. Al contrario, se le DCIL-10/IDUA sono state iniettate dopo che la risposta cellulare B era già stata stabilita, hanno potuto ancora influenzare la risposta anticorpale in modo dipendente da IL-10. Questi risultati supportano lo sviluppo potenziale di un approccio basato su tolDC specifico per l'antigene finalizzato a mitigare le risposte immunitarie avverse successive all'ERT.Lysosomal storage disorders (LSDs) are rare genetic conditions caused by mutations in genes encoding for lysosomal enzymes, leading to the systemic accumulation of undegraded metabolites. Current therapeutic approaches include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation, and gene therapy. ERT remains the standard treatment for many LSDs, consisting in periodic infusion of recombinant human enzymes to provide patients (pts) with a functional enzyme source. Despite its benefits, immune responses against these recombinant enzymes can hinder the effectiveness of the therapy. Consequently, immune tolerance induction (ITI) strategies have become essential and often effective methods for managing immune responses associated with ERT. Tolerogenic dendritic cells (tolDCs) play a critical role in fostering antigen (Ag)-specific tolerance and have shown promise in modulating immune responses in conditions mediated by CD4+ T cells. We established a protocol to generate tolDCs through transduction with a lentiviral vector encoding IL-10 and a specific Ag fused to the invariant chain (Ii). This approach ensures stable presentation of the encoded antigen in both MHC class I and class II contexts, facilitating recognition by CD4+ and CD8+ T cells. Our research aims to develop an Ag-specific TolDC-based strategy to address adverse immune responses, which could serve as adjuvant immunotherapy for ERT-treated pts. To achieve this, we analyzed the enzyme-specific immune response and overall immune status of LSD pts receiving ERT (Mucopolysaccharidosis type IVA, Pompe Disease, and alpha-Mannosidosis). Our findings indicate that the peripheral blood (PB) of ERT-treated LSD pts is enriched with pro-inflammatory cytokines and chemokines. This inflammatory profile is reflected in the cellular compartment, where we observed an increased proportion of neutrophils and activated monocytes compared to healthy controls (HCs). Despite this activated phenotype, monocytes from ERT-treated LSD pts can differentiate into functional DC-10. Additionally, we noted an elevated proportion of T follicular helper (Tfh) cells and antibody(Ab)-producing B cells relative to healthy controls. Correspondingly, variable levels of anti-enzyme Abs were detected in the sera of several patients; however, we were unable to identify an enzyme-specific T-cell response in PB. To elucidate the mechanisms underlying anti-enzyme Ab induction, we evaluated the feasibility of the DCIL-10/Ag approach in a murine model of MPS-I (-L-iduronidase; IDUA-/-). We established an ERT protocol replicating the immune response observed in human pts and determined that Ab production depends on CD4+ T cells. Notably, enzyme-specific T-cell responses were only detectable at the onset of ERT treatment. We generated bone marrow-derived DC (DCIL-10/IDUA) and validated their capacity to modulate the anti-IDUA CD4+ T-cell response in vitro. Furthermore, when DCIL-10/IDUA was administered at the beginning of the ERT treatment, they effectively modulated the anti-IDUA B-cell response. Conversely, if DCIL-10/IDUA were injected after the B-cell response had already been established, they could still influence the antibody response in an IL-10-dependent manner. These findings support the potential development of an enzyme-specific tolDC-based approach aimed at mitigating adverse immune responses following ERT
Devices for minimally invasive liver parenchyma transection: the SICE (Italian Society of Endoscopic Surgery) Italian and International survey
No full textBackgroundsMinimally Invasive Liver Surgery (MILS), encompassing laparoscopic (L-MILS) and robotic (R-MILS) approaches, has revolutionized liver surgery, offering reduced morbidity, shorter hospital stays, and improved outcomes while maintaining oncological efficacy. Despite the widespread use of L-MILS, parenchyma liver transection techniques and devices remain debated. This study investigates the adoption of transection devices (TDs) in MILS among 86 hospitals, focusing on surgical practices, device utilization, and outcomes.MethodsThe Italian Society of Endoscopic Surgery (SICE) endorsed a cross-sectional internet-based survey targeting general and Hepato-Pancreato-Biliary surgeons.ResultsResponses from 86 centers revealed that 77% of institutions is available a robotic platform, with an adoption rate of 87.50% in high-volume centers. L-MILS remains the predominant technique for liver resections, also in case of major hepatectomies, although R-MILS is increasingly utilized. For minor L-MILS, more than 50% of respondents use ultrasonic shears and electrosurgical pencil and advanced bipolar devices, while about 40% of surgeons adopt Cavitronic Ultrasonic Surgical Aspirator (CUSA) in major resections. R-MILS procedures predominantly used Maryland bipolar forceps and vessel sealers, with hybrid techniques (30%) integrating laparoscopic devices (e.g., CUSA) to address robotic device limitations.ConclusionThe minimally invasive approach to liver parenchymal transection is a key component of this surgical procedure. For major hepatectomies, the CUSA device remains the most effective tool, whereas ultrasonic shears, electrosurgical pencil, and advanced bipolar devices are more suited for minor resections. Despite limited access to specialized instruments, R-MILS achieves favorable outcomes in liver transection by employing the crash-clamp technique or hybrid strategies
Significance loss and political vs. religious terrorism: a textual analysis
No full textDrawing on Significance Quest Theory, we applied the LIWC-based textual analysis to the Honor Dictionary to investigate lone-actors terrorists’ rhetoric. Specifically, we examined texts from the Extremist Manifesto Database (EMD) and compared writings by terrorists driven by political ideologies (left & right-wing, ethno-nationalists, and anti-government, N=65) with those of terrorists motivated by religious ideologies (N=23). Given that religious extremists are particularly sensitive to honor threats, we expected that religious terrorists’ rhetoric would have been more tinged in honor loss than political terrorists’ one. Indeed, we found that lone-actor religious terrorists' rhetoric, compared to lone-actors’ political one, contained more honor-loss words. Contrary to our predictions instead, we did not find any difference with respect to honor-gain words. Notably, this is the first research to use the Honor Dictionary to linguistically measure the activation of the need for significance, demonstrating a strong correlation with extreme ideologies endorsement. Further, our research supports the hypothesis that extreme ideologists’ rhetoric reflects significance loss feelings
Blockade of CD155 and CD276 by Monoclonal Antibodies Fosters Immune Tolerance and Promotes Stable Engraftment of iPSC-Derived Islets in Allogeneic Humanized Mice
Full text linkInduced pluripotent stem cell (iPSC)-derived pancreatic islets represent a promising therapeutic approach for restoring insulin independence in type 1 diabetes (T1D). However, their clinical success remains critically dependent on overcoming rejection mediated by innate and adaptive immune responses. Current immunosuppressive therapies pose significant long-term risks and only partially control alloimmune and autoimmune reactions. Targeted immunomodulation using monoclonal antibodies is a safer, more precise alternative. Here, we explored the impacts of blocking CD276 (B7-H3) and CD155 (PVR), activating ligands involved in immune recognition and regulation, on the survival and in vivo maturation of iPSC-derived endocrine progenitors (EPs) into functional pancreatic islets. Using a humanized mouse model, we demonstrated that dual blockade of CD276 and CD155 markedly reduced NK cell-mediated graft rejection, prevented CD14+ monocyte activation, and limited overall immune infiltration. In addition, CD155 blockade increased PD-1 levels on activated CD8+ T cells and significantly enhanced regulatory T cell (Treg) expansion and function, thereby promoting graft tolerance. Combined treatment prolonged engraftment and facilitated the maturation of EPs into functional, insulin-secreting cells, as indicated by increased human C-peptide levels and glucose responsiveness 4 weeks post-transplantation. Our findings highlight CD276/CD155 blockade as a novel immunomodulatory strategy to support tolerance and the functional maturation of iPSC-derived pancreatic grafts in T1D
Procedural Moral Progress: Comments on Philip Kitcher’s «Moral Progress»
No full textThe debate on the concept of moral progress has receive renewed attention in the last decade7. Within this debate, Philip Kitcher’s Moral Progress represents an insightful, though provoking, and inspiring contribution
Metabolic Syndrome and Schizophrenia: Adding a Piece to the Interplay Between the Kynurenine Pathway and Inflammation
No full textThe biology of schizophrenia is highly complex and multifaceted. Numerous efforts have been made over the years to disentangle the heterogeneity of the disease, gradually leading to a more detailed understanding of its underlying pathogenic mechanisms. Two cardinal elements in the pathophysiology of schizophrenia are neuroinflammation and alterations of neurotransmission. The kynurenine (KYN) pathway (KP) is of particular importance because it is inducted by systemic low-grade inflammation in peripheral tissues, producing metabolites that are neuroactive (i.e., modulating glutamatergic and cholinergic neurotransmission), neuroprotective, or neurotoxic. Consequently, the KP is at the crossroads between two primary systems involved in the pathogenesis of schizophrenia. It bridges the central nervous system (CNS) and the periphery, as KP metabolites can cross the blood–brain barrier and modulate neuronal activity. Metabolic syndrome plays a crucial role in this context, as it frequently co-occurs with schizophrenia, contributing to a sub-inflammatory state able to activate the KP. This narrative review provides valuable insights into these complex interactions, offering a framework for developing targeted therapeutic interventions or precision psychiatry approaches of the disorder
Myocardial microvascular function assessed by cardiovascular magnetic resonance first-pass perfusion in patients with Takotsubo syndrome
No full textObjective: The purpose of this study was to explore microvascular function impairment using first-pass cardiovascular magnetic resonance (CMR) in patients with Takotsubo syndrome (TS). Moreover, we explored myocardial microcirculation in patients with TS and related this to demographic data, cardiovascular risk factors, clinical parameters, cardiac biomarkers, and cardiac function. Methods: This retrospective study performed CMR first-pass perfusion scans in 42 consecutive patients with TS (37 females, 70.6 ± 9.4 years). Moreover, we included 44 sex- and age-matched healthy controls (33 females, 66.4 ± 10.5 years). CMR-derived myocardial microcirculation function was analyzed and compared between TS patients and controls. Results: Compared to age-, sex-, and cardiovascular risk factors-matched control group, TS patients demonstrated a lower perfusion index (PI) (0.140 ± 0.060 vs. 0.182 ± 0.056, p = 0.001). In multivariable analysis with adjustment for demographic data and cardiovascular risk factors, an impairment in PI was independently associated with left ventricle ejection fraction (β coefficient = 3.793, p = 0.001) and T2 mapping (β coefficient = −4.316, p = 0.001). Conclusion: TS patients exhibited myocardial microvascular dysfunction, which was non-invasively assessed using first-pass CMR. This impaired myocardial microvascular function was found to be independently associated with left ventricular ejection fraction and myocardial edema. Key Points: Question Can cardiovascular magnetic resonance (CMR) cardiac MR first-pass perfusion help to better understand Takotsubo pathophysiology by exploring microvascular impairment? Findings CMR first-pass perfusion revealed significant microvascular dysfunction during the acute phase of Takotsubo syndrome, independently associated with left ventricular ejection fraction and myocardial edema. Clinical relevance Identifying an abnormal microvascular network using non-invasive biomarkers could enhance risk stratification and guide tailored management during the acute phase of Takotsubo syndrome
Pathophysiology and clinical use of agents with vasodilator properties in acute heart failure. A scientific statement of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)
No full textAcute heart failure (AHF) affects millions of people each year and vasodilators have been a central part of treatment for over 25 years. The haemodynamic effects of vasodilators vary considerably among individual agents. Some vasodilators, such as nitrates, primarily act on the venous system by redistributing the circulating blood volume away from the heart towards the venous capacitance system. Other vasodilators, such as nesiritide, lead to balanced vasodilatation in the arteries and veins, decreasing left ventricular afterload and preload. Considering mechanisms of action, intravenous vasodilators are thought to be effective in patients with AHF, particularly in those with acute pulmonary oedema, where increased cardiac filling pressures and elevated systemic blood pressures occur in the absence of, or with minimal systemic fluid accumulation. However, the 2021 European heart failure guidelines have downgraded the use of vasodilators due to two recent studies and several contemporary meta-analyses failing to show benefit in terms of survival. Thus, there remains no firm recommendation suggesting the use of vasodilator treatment over usual care. In addition, despite repeated efforts to develop new vasodilatory agents, no novel therapy has outperformed traditional AHF management. In parallel with the development of novel vasodilators, changing the design of clinical trials for AHF to consider phenotype diversity of AHF patients remains an unmet need. New randomized clinical trials should particularly focus on subgroups that may mechanistically derive benefit from vasodilators, which may entail moving enrolment of patients to clinical settings close to moment of decompensation, such as the emergency department