IRIS Università degli Studi dell'Aquila
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LGALS3BP antibody-drug conjugate enhances tumor-infiltrating lymphocytes and synergizes with immunotherapy to restrain neuroblastoma growth
Get PDFBackground: LGALS3BP, also referred as Gal-3BP, Mac2-BP, or 90 K, is a heavily glycosylated, secreted protein prominently localized at the surface of cancer-derived extracellular vesicles (EVs). Its levels are significantly elevated in various types of cancer, including neuroblastoma, and are generally associated with advanced disease and tumor progression. Our previous research has shown that LGALS3BP is an effective target for ravtansine (DM4)-based Antibody-Drug Conjugate (ADC) therapy in multiple preclinical models. Methods: We assessed total and extracellular vesicles (EVs)-associated LGALS3BP through ELISA assay in serum of a pseudometastatic neuroblastoma model to evaluate the correlation of LGALS3BP levels with tumor dissemination. We employed a syngeneic neuroblastoma mouse model using murine neuroblastoma NXS2 cells overexpressing human LGALS3BP in order to evaluate immunogenic cell death (ICD) induced by anti-LGALS3BP ADC therapy and investigated the nature of the tumor immune infiltrate by cytofluorimetry. Furthermore, we designed a six-arm in vivo experiment to evaluate the efficacy of ADC in combination with an immune check-point inhibitor (ICI) anti-PD-1. Finally, a rechallenge assay was conducted on cured mice to assess the presence of immunological memory. Results: Here, we report that circulating and EVs-associated LGALS3BP levels significantly correlate with neuroblastoma progression and dissemination. Moreover, we show that in the syngeneic NXS2 neuroblastoma model, DM4 treatment induces cell surface expression of ICD markers calreticulin, HSP70, and HSP90, and an increased PD-L1 expression in vitro, followed by enhanced tumor-infiltrating lymphocytes in vivo. Notably, the combination therapy of anti-LGALS3BP-targeting ADC with anti-PD-1 results in a higher inhibition of tumor growth and prolonged survival compared with either agent given alone. Rechallenge assay reveals that mice previously treated and cured with the ADC retain immune memory, suggesting the therapy’s ability to induce a durable and protective antitumor immune response. Conclusions: Our findings establish that circulating LGALS3BP is a potential biomarker for liquid biopsy and uncover this protein as a suitable target for therapeutic strategies combining 1959-sss/DM4 ADC with an anti-PD-1 ICI for the treatment of LGALS3BP expressing neuroblastoma
Effectiveness and safety of dual antiplatelet therapy in patients with minor ischemic stroke or transient ischemic attack and cancer: A secondary analysis of the READAPT study
Get PDFIntroduction: Patients with ischemic stroke or transient ischemic attack (TIA) and cancer face unique risks of recurrent ischemic events and bleeding. It is unclear whether this increased risk is present even in patients with minor ischemic stroke or transient ischemic attack (TIA) receiving dual antiplatelet therapy (DAPT). This study aimed to evaluate the impact of cancer on the short-term outcomes after DAPT in patients with non-cardioembolic minor ischemic stroke or high-risk TIA. Patients and methods: This was a secondary analysis of the prospective multicentric READAPT study (NCT05476081), including patients with non-cardioembolic minor ischemic stroke (NIHSS ⩽ 5) or high-risk TIA (ABCD2 ⩾4) who initiated DAPT within 48 h of symptom onset. The primary effectiveness outcome was the 90-day risk of new ischemic stroke or other vascular events (TIA, myocardial infarction, death due to vascular causes). Secondary outcomes included 90-day mRS score distribution and all-cause mortality. The primary safety outcome was the 90-day risk of any bleeding, with secondary safety outcomes including 24-h hemorrhagic transformation. We used Inverse Probability Weighting to compare outcomes between patients with and without cancer. Results: From 2278 patients in the READAPT study cohort, we included 1561 patients (mean age 70.3 ± 11.7 years; 65.4% males), of whom 206 (13.2%) had cancer, categorized as either active (27.7%) or in remission (72.3%). After weighting, overall cancer patients had a higher risk of 90-day new ischemic stroke or other vascular events (weighted HR 1.78, 95% CI 1.20-2.63, p = 0.004) and worse 90-day mRS score distribution (OR 1.24, 95% CI 1.10-1.41, p < 0.001) compared to patients without cancer. The 90-day risk of bleeding did not differ between cancer and no-cancer groups overall. When analyzing cancer subgroups, patients with active cancer had significantly higher risk of 90-day ischemic stroke or other vascular (weighted HR 2.75, 95% CI 1.70-4.45, p < 0.001) and any bleeding (weighted HR 2.51, 95% CI 1.27-4.97, p = 0.008) events compared to no-cancer patients. In contrast, patients with cancer in remission had comparable risks to those without cancer. Furthermore, hematological malignancies were associated with a substantially higher risk of 90-day new ischemic stroke or other vascular events compared to solid tumors (weighted HR 8.15, 95% CI 5.06-13.14, p < 0.001). Conclusions: Patients with minor ischemic stroke or high-risk TIA and active cancer have increased risk of ischemic and bleeding events after DAPT. Conversely, patients with cancer in remission have similar outcomes compared to those with no cancer
Enhancement of Short-Term prediction capabilities of Inter-Area Grid Oscillations with a Multi-Variate Ensemble-based Method.
Get PDFThe actual and future even higher penetration of renewable energy sources into the
power grid sets challenging issues for transmission system operators, especially
concerning the hard-to-solve problem of inter-area electromechanical oscillations.
Despite the useful existing monitoring systems, the possibility of having predictive
monitoring features for such phenomena could be an appealing tool. The work presented
in this paper aims to assess the possibility of enhancing the predictive monitoring features
offered by machine learning techniques based on the combination of ensemble methods
and Long-Short-Term Memory units using multi-variate methods. The development steps
of a multi-variate prediction strategy are presented together with the assessment of its
performance versus uni-variate solutions. The assessment takes into account different
kinds of datasets, taken from real grid measurements, and strategy configurations. Either
transient low frequency oscillation phenomena or normal grid operation are considered
as representative cases of real-world scenarios. Finally, some preliminary considerations
about improving prediction performance and the limitations are outlined
Identifying Cladribine prescription pattern in MS: an Italian multicentre study
Get PDFBackground:
Characterizing Cladribine tablets prescription pattern in daily clinical practice is crucial for optimizing multiple sclerosis (MS) treatment. Objectives: To describe efficacy, safety profile and new disease-modifying therapy (DMT) prescriptions following Cladribine treatment. Design: Independent retrospective cohort study in patients followed at six Italian MS centres. Methods: Patients diagnosed with relapsing MS (RMS) according to 2017 McDonald criteria, who initiated Cladribine between January 2019 and May 2023, were included. A generalized linear regression model was built for the outcome DMT after Cladribine course. Heatmaps were generated based on weighted pivot tables to visualize the proportion of patients requiring DMT post-Cladribine. Results: A total cohort of 352 patients was enrolled, 134 naïve to any DMT, 218 switchers from other DMTs. The last DMT was an injectable first-line DMT for 48 (22%) patients, oral first-line DMT for 141 (64.7%) patients, SP1 inhibitor-Fingolimod for 23 (10.6%) patients, and Natalizumab for 6 (2.7%) patients. Overall, Cladribine was efficacious and well tolerated, 12% of patients required a new DMT prescription after a median time of 24 months. The regression model revealed that patients aged >40 years at Cladribine prescription had a 16% decrease in likelihood of receiving a new DMT. Heatmaps showed patients previously on Fingolimod had a lower rate (72.2%) of being free from therapy after Cladribine. Conclusion: In our multicentric real-world Italian study, Cladribine therapy is generally effective during the investigated follow-up period. Understanding key characteristics of patients responding best to Cladribine can help tailor therapeutic strategies for optimal outcomes
La scuola elementare in Abruzzo dall’Unità d’Italia all’avvento del fascismo. Un profilo storico-statistico
No full textOn Structured Perturbations of Positive Semigroups
No full textIn this thesis we study perturbation results for the generator A of a positive C_0--semigroup on a Banach lattice X. We generalize results that hold for an AM- or AL-space X and extend them to an arbitrary Banach lattice X in case the perturbation can be factorized as P=BC via an AM- or AL-space U. This allows to deal with applications on (infinite dimensional) reflexive Banach spaces, which are a priori excluded if X is an AM- or an AL-space.
First, B and C are assumed to be positive operators satisfying the spectral condition r(CR(\lambda,A_{-1})B)\omega_0(A). We then prove that the generation results obtained in this case still hold when B and C are not necessarily positive, but only dominated by positive operators. These abstract results are applied to domain perturbations of generators, a heat equation with boundary feedback and perturbations of the first derivative.
Combining the previous results we then deal with "doubly unbounded" perturbations P:Z\to X_{-1}, provided they can be factorized as P=BC via U=\mathbb{R}^N. In this context, we prove a Staffans--Weiss type perturbation result. We show that the classically assumed admissibility and invertibility conditions for the associated input--output map \mathcal{F}_\infty follow from the (much simpler to verify) spectral condition mentioned above. The abstract results are applied to domain perturbations and finite rank perturbations of the first derivative
Hydroelastic analysis of partially or totally immersed Mindlin plates with a hybrid isogeometric-based approach
No full textIn this study, the dynamic characteristics of a cantilevered Mindlin plate, partially or totally in contact with fluid on both sides, are examined using the proposed hybrid isogeometric finite element – boundary element framework. The interaction problem is divided into two parts through the implementation of the linear hydroelasticity theory, allowing for the independent treatment of structural and fluid problems. In the structural part of the analysis, the thick plate is modeled as first-order shear deformable by adopting Reissner–Mindlin plate theory, with the material assumed to be homogeneous and isotropic. The resulting eigenvalue problem is then solved by the isogeometric finite element method (IGAFEM). In the second part of the analysis, assuming the fluid is ideal and incorporating the in vacuo dynamic characteristics as boundary conditions, fluid-structure interaction effects are determined by the isogeometric boundary element method (IGABEM) in terms of generalized added mass coefficients. Subsequently, parametric studies for various plate thicknesses and submergence depths are conducted. The analysis reveals that wet natural frequencies differ noticeably from their in vacuo counterparts due to the presence of the free surface of the fluid. In addition, the effect of the radiated free surface waves from the vibrating structure are included into the mathematical model by imposing linearized free surface condition, through the frequency-dependent added mass and hydrodynamic damping effects of the fluid. The numerical accuracy of the proposed approach is verified against the commercial finite element software ANSYS, showing favourable agreement in the predicted natural frequencies and corresponding mode shapes
Asymptotic Behavior of a transmission Heat/Piezoelectric smart material with internal fractional dissipation law
No full textIn this paper, we analyze the stability of a system involving a heat-conducting copper rod and a magnetizable piezoelectric beam, where fractional damping influences the longitudinal displacement of the beam's centerline. The coupled dynamics are governed by partial differential equations that incorporate heat diffusion in the copper rod and piezoelectric effects in the beam, including both mechanical and electrical interactions. Previous research has extensively studied piezoelectric systems and heat transfer dynamics separately, but the combined effect with fractional damping presents a novel challenge. Our investigation employs semi-group theory and multiplier methods to establish a polynomial stability result that is dependent on the order of the fractional derivative, offering insights into the interplay between heat transfer and piezoelectric behavior under fractional damping, which is critical for developing robust and efficient energy harvesting devices and structural control mechanisms
