IRIS UniSR (’Università Vita-Salute San Raffaele)
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The Shu complex interacts with the replicative helicase to prevent mutations and aberrant recombination
No full textHomologous recombination (HR) is important for DNA damage tolerance during replication. The yeast Shu complex, a conserved homologous recombination factor, prevents replication-associated mutagenesis. Here we examine how yeast cells require the Shu complex for coping with MMS-induced lesions during DNA replication. We find that Csm2, a subunit of the Shu complex, binds to autonomous-replicating sequences (ARS) in yeast. Further evolutionary studies reveal that the yeast and human Shu complexes have co-evolved with specific replication-initiation factors. The connection between the Shu complex and replication is underlined by the finding that the Shu complex interacts with the ORC and MCM complexes. For example, the Shu complex interacts, independent of other HR proteins, with the replication initiation complexes through the N-terminus of Psy3. Lastly, we show interactions between the Shu complex and the replication initiation complexes are essential for resistance to DNA damage, to prevent mutations and aberrant recombination events. In our model, the Shu complex interacts with the replication machinery to enable error-free bypass of DNA damage
A High-Fiber Plant-Based Diet in Myeloma Precursor Disorders – Results from the NUTRIVENTION Clinical Trial and Preclinical Vk*MYC Model
No full textModulation of the gut microbiota to block the expansion of gut-born T helper-17 lymphocytes and limit aggressiveness of multiple myeloma
Get PDFWhile asymptomatic smoldering multiple myeloma (SMM) holds an overall risk of progression to multiple myeloma (MM) at 10% per year, most of the patients affected by SMM remain untreated. Poor quality of the diet, elevated body mass index, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in SMM-to-MM progression. Indeed, our group previously demonstrated that the intestinal microbiota and gut-born T helper 17 (Th17) lymphocytes may act as drivers of MM progression in mice. Similarly, we reported that higher levels of bone marrow (BM) Interleukin-17 (IL-17) predicted accelerated disease progression in SMM patients.
Based on these premises, I focused my thesis work on targeting the gut microbiota-immune axis aiming at intercepting the trajectory of SMM-to-MM progression. I also investigated if microbiota-based interventions would improve susceptibility to immune checkpoint blockade (ICB).
To modulate the gut microbiota, transgenic Vk*MYC mice at the phase of asymptomatic SMM were treated with the human commensal bacteria Prevotella melaninogenica and/or anti-PD-L1 antibodies which were previously associated with reduced MM aggressiveness. Administration of P. melaninogenica to SMM mice significantly delayed evolution to MM. Mechanistically, P. melaninogenica, by direct bacterium-immune cell contact and through the release of short-chain fatty acids (SCFAs), prevented CD11c+ mononuclear phagocytes (MPs) from skewing towards a pro-Th17 phenotype. By restraining Th17 cell expansion, P. melaninogenica also synergized with anti-PD-L1 antibodies to promote tumor control and limited inflammatory adverse events aggravated by anti-PD-L1.
Because dietary fibers constitute the substrate for microbiota-dependent biosynthesis of SCFAs, we administered a high fiber diet to SMM Vk*MYC mice, which resulted in increased production of SCFAs and a significant improvement of progression-free survival. Consistently, the BM of high fiber-treated mice was less infiltrated by proinflammatory MPs and Th17 cells while enriched in IFNg-producing T lymphocytes.
In conclusion, modulation of the gut microbiota with probiotics or prebiotics significantly impacted the trajectory of SMM-to-MM evolution in mice and ameliorated the efficacy of ICB. These findings might represent the basis to design novel treatments for patients affected by plasma cell dyscrasias.Nonostante il rischio di progressione da mieloma multiplo smoldering (SMM) a mieloma multiplo (MM) sia del 10% all’anno, molti dei pazienti affetti da SMM non vengono trattati. Tra i fattori di rischio per la progressione di malattia vi sono l’aderenza a una dieta di scarsa qualità, un elevato indice di massa corporea, l’alterazione dell’omeostasi intestinale (disbiosi), uno stato generale di infiammazione e disfunzione immunitaria. Il nostro gruppo di ricerca ha precedentemente dimostrato che il microbiota intestinale e i linfociti T helper 17 (Th17) originati nell’intestino possono favorire l’evoluzione del MM nei modelli murini. Allo stesso modo, livelli elevati di Interleuchina-17 (IL-17) nel midollo osseo predicono un’evoluzione di malattia più accelerata nei pazienti con SMM.
Sulla base di queste premesse, il mio lavoro di tesi si è concentrato sullo studio di strategie volte a modulare l’asse microbiota-immunità ed intercettare l’evoluzione da SMM a MM. Ulteriore obiettivo del progetto è stato valutare se la modulazione del microbiota migliorasse la sensibilità al trattamento con inibitori dei checkpoint immunitari.
Per modulare il microbiota intestinale, topi transgenici Vk*MYC nella fase di SMM sono stati trattati con il batterio commensale umano Prevotella melaninogenica, precedentemente associato a una minore aggressività del MM, e/o con anticorpi anti-PD-L1. La somministrazione di P. melaninogenica ai topi SMM ha ritardato significativamente l’evoluzione verso MM. Tramite contatto diretto batterio-cellula immunitaria e mediante il rilascio di metaboliti quali acidi grassi a catena corta, P. melaninogenica ha limitato il differenziamento di cellule presentanti l'antigene verso un fenotipo pro-infiammatorio riducendo i livelli di cellule Th17 nel midollo osseo. Inoltre, P. melaninogenica ha agito in sinergia con gli anticorpi anti-PD-L1 rallentando ulteriormente la progressione della malattia e ha limitato gli eventi avversi infiammatori aggravati dall’utilizzo di anti-PD-L1.
Poiché le fibre alimentari costituiscono il substrato per la biosintesi di acidi grassi a catena corta da parte del microbiota, abbiamo somministrato una dieta ad alto contenuto di fibre a topi Vk*MYC in fase SMM. Tale alimentazione ha portato a un aumento della concentrazione di acidi grassi a catena corta e un ritardo significativo nella progressione della malattia. Il midollo osseo dei topi trattati con dieta ricca di fibre conteneva meno cellule dendritiche pro-Th17 e linfociti Th17, mentre si è arricchito di linfociti T produttori di IFNγ.
In conclusione, la modulazione del microbiota intestinale con probiotici o prebiotici ha significativamente influenzato l’evoluzione di malattia da SMM a MM nei topi migliorando l’efficacia dell’immunoterapia. L’insieme di questi risultati fornisce una base per la progettazione di nuovi trattamenti per pazienti affetti da discrasie plasmacellulari
Survival Following CDK4/6 Inhibitor Therapy for Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer
No full textIMPORTANCE Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor–positive, ERBB2 (formerly HER2 or HER2/neu)–negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear. OBJECTIVE To evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor–positive, ERBB2–negative metastatic breast cancer following progression with ET plus CDK4/6i. DESIGN, SETTING, AND PARTICIPANTS The multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor–positive, ERBB2–negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy. MAIN OUTCOMES AND MEASURES The primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause. RESULTS In 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2–negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P < .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P < .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04). CONCLUSIONS AND RELEVANCE In this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups
Length of stay after colorectal surgery in Italy: the gap between “fit for” and “actual” discharge in a prospective cohort of 4529 cases
Get PDFBackground It is common to observe a gap between the day on which the discharge criteria are reached and the actual day of discharge after colorectal surgery. The aim of this study is to understand the reasons for this difference and its clinical impact on the overall length of stay (LOS). Methods All patients enrolled in the prospective iCral3 study were analyzed regarding any difference and reason between the "fit for discharge" (FFD) and "actual discharge" (AD) dates. The association between the gap and the LOS in the whole population was then assessed through a multivariate regression model including other confounding variables. Results The analysis included 4529 patients, with a median [IQR] LOS of 6 [4-8] days. The median [IQR] LOS was 6 [4-8] days in the no-gap group (3,910 patients, 86.3%), significantly lower (p < .001) than 7 [6-10] days in the gap group (619 patients, 13.7%). Among the gap reasons, the "need for postoperative rehabilitation" compared to "not willing to return home" and "social constraints" was associated with the longest LOS (9 [6.0-12.5] days, p < 0.001 vs other reasons). The existence of the gap independently determined a 2.3-day lengthening of LOS. Conclusions Among other factors, the gap between FFD and AD had an independent impact on LOS. The most frequent reasons for this gap were "not willing to return home" and "social constraint", while the "need for postoperative rehabilitation" had the greater clinical impact
Sequential endoscopic and laparoscopic treatment for choledocholithiasis: a 30-year experience in the era of evolving techniques
No full textBackground: Sequential endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy (EST) followed by laparoscopic cholecystectomy (LC) is a standard minimally invasive approach for treating concomitant gallbladder and common bile duct stones. This study presents a 30-year experience with this strategy and compares its outcomes with emerging single-session techniques, including laparoscopic common bile duct exploration (LCBDE) and laparoendoscopic rendezvous (LERV). Methods: Between October 1991 and December 2020, a total of 350 patients (mean age 65 years, range 35–80) underwent EST and/or ERCP followed by LC in a sequential treatment protocol for choledocholithiasis. Patient demographics, intra- and post-procedural variables, complication rates, and long-term outcomes were retrospectively reviewed. The success rate of stone clearance, morbidity, mortality, and recurrence rates were calculated. Results: Of the 350 treated patients, 240 (68.6%) had confirmed CBD stones. ERCP/EST achieved stone clearance in a single-session in 180 patients (75%). Among the remaining cases, additional ERCP sessions were required, and 14 patients ultimately failed to achieve endoscopic clearance. Three patients discontinued treatment (two declined a second ERCP and one refused LC after endoscopic clearance). Laparoscopic cholecystectomy was aborted in three patients (one due to anesthetic intolerance and two due to severe inflammation). Post-procedural complications occurred in 21 patients (6%), predominantly comprising mild pancreatitis and minor bile leak, or wound infections. No mortality was observed. Median hospital stay was 5.5 days. Recurrent CBD stones were observed in 15 patients (4.3%), managed with repeat ERCP (8 cases) or surgical revision (7 cases). Conclusions: While sequential therapy remains an effective and widely adopted technique, the growing body of evidence on single-session, minimally invasive strategies such as LCBDE and LERV offers valuable alternatives in selected scenarios. Each approach presents specific advantages and challenges, and the choice of treatment should be guided by individual patient characteristics, clinical context and available institutional expertise
[18F]FDG PET/MRI vs sentinel node biopsy for axillary staging of early breast cancer patients. A prospective single-arm trial
No full textBackground: Two randomized controlled trials demonstrated the non-inferiority of axillary surgery omission in selected early breast cancer patients. However, clinicians remain hesitant to forgo sentinel lymph node biopsy due to its potential therapeutic implications. A reliable imaging modality for nodal metastases detection could potentially replace surgery. This trial prospectively evaluated the accuracy of hybrid [18F]FDG PET/MRI in detecting axillary lymph nodes macro-metastases in women with early breast cancer. Methods: This is a prospective interventional single-arm monocentric trial including patients with breast cancer without nodal involvement on standard preoperative imaging and eligible for upfront surgery. Between June 2020 and April 2024 recruited patients underwent [18F]FDG PET/MRI before surgery. Two radiologists and two nuclear medicine physicians, all blinded, independently reviewed the images. Findings: A total of 246 patients were included. Five had bilateral disease, leading to the evaluation of 251 axillae. Mean (SD) age at surgery was 56.3 (10.7) years and mean (SD) tumor size was 17.5 (13.0) mm at final pathology. Macro-metastatic axillary lymph nodes were found in 61 cases (24.3 %). [18F]FDG PET/MRI identified 43 (70.5 %) of these cases, and significantly outperformed both [18F]FDG PET and MRI alone, which identified 36 (59.0 %; p = 0.016) and 25 (41.0 %; p < 0.001) cases, respectively. Negative predictive value was higher for [18F]FDG PET/MRI (89.4 %) than [18F]FDG PET (86.4 %, p = 0.021) and MRI (82.9 %, p0.001 <) alone. Interpretations: [18F]FDG PET/MRI detected 70.5 % of cases with macro-metastatic axillary lymph nodes in patients with clinically negative axilla, with greater accuracy than [18F]FDG PET or MRI alone. Advanced imaging might help refine the surgical strategy for axillary staging. Trial registration: ClinicalTrials.Gov ID NCT0482964
Overall impact of tethering and of its symmetric and asymmetric subtypes on early and long-term outcome of transcatheter edge-to-edge repair of significant mitral valve regurgitation
No full textBackground: Tethering is a common condition of the mitral valve apparatus in the presence of significant regurgitation. Its impact on outcomes of transcatheter edge-to-edge repair (TEER) remains poorly characterized. Methods: We appraised the prevalence, features, procedural details, and outcomes of patients with or without mitral valve tethering in a prospective multicenter observational study. The primary endpoint was the risk of cardiac death or rehospitalization for heart failure at mid-term follow-up. Results: We included 2238 patients, 1467 (65.5 %) without tethering and 771 (34.5 %) with tethering (487 [21.8 %] with symmetric and 284 [12.7 %] with asymmetric tethering). Several differences in baseline features were evident among groups, yet procedural results were similar. After a median of 14 months, rates of cardiac death or rehospitalization for heart failure was significantly higher at unadjusted analysis in patients with tethering (191 [24.8 %] vs. 272 [18.5 %] in those without tethering, p = 0.001), but weres similar between tethering subtypes (p = 0.666). At adjusted analysis, the presence of any tethering was no longer a significant predictor of cardiac death or rehospitalization for heart failure, and the same results were obtained focusing on tethering subtypes (all p > 0.05). Conclusions: Tethering is common among patients with an indication to TEER, and is associated with adverse baseline and procedural features. In spite of this, device and procedural success rates are not significantly impacted by the presence of tethering that does not even have a negative prognostic effect at follow-up. Accordingly, tethering should not be considered a contraindication to TEER in suitable patients
Exploring gender differences in patient engagement: a scoping review
No full textSummary. Introduction. Patient-centered healthcare emphasizes patient engagement as a critical factor in improving outcomes. Despite gender’s impact on healthcare, gender-specific dimensions of engagement remain underexplored. Objective. To explore, map, and synthesize gender differences in patient engagement, providing an in-depth analysis of the most effective tools for enhancing engagement. Methods. A scoping review was conducted following JBI guidelines and the PRISMA-ScR checklist. Two authors searched MEDLINE, CINAHL, PsycINFO, Embase, and Scopus independently using a blinded selection process. Results. This review included five studies, which explored engagement tools across gender differences and identified effective strategies. Mobile health interventions with structured tasks and therapist support enhanced engagement among women by promoting accountability, while gamified interventions promoting participation through competition and social interaction improved engagement among men. Peer-led, gender-affirming programs tailored to transgender women improved engagement by addressing stigma and identity needs. Text messaging interventions promoted high engagement across genders and supported long-term behavior change. Conclusions. Engagement levels vary by gender and are influenced by education and age. Further research is needed to determine the most effective engagement tool, as the included studies used different outcome measures and lacked validated scales, preventing direct comparisons
Brief Report: New HIV Diagnoses in PrEP-Experienced and PrEP-Naive Persons in the ICONA Cohort
No full textBackground:The best therapeutic management for people with HIV (PWH) who have a history of preexposure prophylaxis (PrEP) is still debated.Objectives:The aim of this study was to describe recent HIV infections in PrEP users compared with people never exposed to PrEP.Methods:Multicentre retrospective analysis evaluating all recent HIV infections from 2018 to 2021 within the Italian Cohort Naive Antiretrovirals. PWH, PrEP experienced or not, were compared using χ2 test and Wilcoxon rank-sum test for categorical and continuous variables, respectively. A mixed linear model was used to estimate the change of the estimated mean HIV-RNA in the first year after ART initiation, according to PrEP exposure.Results:Fifty-one recent HIV diagnoses were identified, 9 in PrEP-experienced people, with an increasing temporal trend over the study period. Clinicians often initiated four-drug ART or NRTI-avoiding regimens in PrEP-experienced individuals, but this approach did not result in better viral decay or faster virologic suppression compared with traditional three-drug regimens. All achieved viral suppression during follow-up, within a median of 5.1 (IQR, 3.2-8.7) months in PWH never exposed to PrEP and 5.2 (IQR 3.2-9.4) months in PrEP-experienced PWH (P = 0.937). M184I/V was the most common mutation in PrEP-experienced individuals (37.5%).Conclusions:An increasing number of people newly diagnosed with HIV report previous use of PrEP. All PrEP-experienced PWH in ICONA cohort have achieved rapid virologic suppression, even in cases with the presence of transmitted viral mutation