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The parallel hydraulic hybridization, thanks to its simplicity and high specific power, is a suitable solution for the retrofitting of off-highway vehicles subject to work cycles with frequent stop-and-go. This work is focused on the potential of the low-cost parallel hybrid solutions, i.e. characterized by current-technology components, for a specific class of heavy vehicles: city buses. After functional sizing, the hybrid vehicle was modelled and simulated in the Amesim environment. The comparison with the non-hybridized reference vehicle highlighted an interesting consumption reduction, which in any case varies with the type of route. Finally, an optimization of the hybrid vehicle was carried out by means of genetic algorithms, which led to a further, and not negligible, consumption reduction compared to the hybridized version. Optimization, therefore, can be seen as a tool to overcome those minimum benefit thresholds that manufacturers consider as necessary for the industrialization and marketing of new energy recovery systems.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a very low survival rate at 5 years. The use of chemotherapeutic agents results in only modest prolongation of survival and is generally associated with the occurrence of toxicity effects. Antibody-based immunotherapy has been proposed for the treatment of PDAC, but its efficacy has so far proved limited. The proteoglycan glypican-1 (GPC1) may be a useful immunotherapeutic target because it is highly expressed on the surface of PDAC cells, whereas it is not expressed or is expressed at very low levels in benign neoplastic lesions, chronic pancreatitis, and normal adult tissues. Here, we developed and characterized a specific mouse IgM antibody (AT101) targeting GPC1. Methods We developed a mouse monoclonal antibody of the IgM class directed against an epitope of GPC1 in close proximity to the cell membrane. For this purpose, a 46 amino acid long peptide of the C-terminal region was used to immunize mice by an in-vivo electroporation protocol followed by serum titer and hybridoma formation. Results The ability of AT101 to bind the GPC1 protein was demonstrated by ELISA, and by flow cytometry and immunofluorescence analysis in the GPC1-expressing "PDAC-like" BXPC3 cell line. In-vivo experiments in the BXPC3 xenograft model showed that AT101 was able to bind GPC1 on the cell surface and accumulate in the BXPC3 tumor masses. Ex-vivo analyses of BXPC3 tumor masses showed that AT101 was able to recruit immunological effectors (complement system components, NK cells, macrophages) to the tumor site and damage PDAC tumor tissue. In-vivo treatment with AT101 reduced tumor growth and prolonged survival of mice with BXPC3 tumor (p

Abstract Background Nanoparticles represent one of the most important innovations in the medical field. Among nanocarriers, polymeric nanoparticles (PNPs) attracted much attention due to their biodegradability, biocompatibility, and capacity to increase efficacy and safety of encapsulated drugs. Another important improvement in the use of nanoparticles as delivery systems is the conjugation of a targeting agent that enables the nanoparticles to accumulate in a specific tissue. Despite these advantages, the clinical translation of therapeutic approaches based on nanoparticles is prevented by their interactions with blood proteins. In fact, the so-formed protein corona (PC) drastically alters the biological identity of the particles. Adsorbed activated proteins of the complement cascade play a pivotal role in the clearance of nanoparticles, making them more easily recognized by macrophages, leading to their rapid elimination from the bloodstream and limiting their efficacy. Since the mouse is the most used preclinical model for human disease, this work compared human and mouse PC formed on untargeted PNPs (uPNPs) and targeted PNPs (tPNPs), paying particular attention to complement activation. Results Mouse and human serum proteins adsorbed differently to PNPs. The differences in the binding of mouse complement proteins are minimal, whereas human complement components strongly distinguish the two particles. This is probably due to the human origin of the Fc portion of the antibody used as targeting agent on tPNPs. tPNPs and uPNPs mainly activate complement via the classical and alternative pathways, respectively, but this pattern did not affect their binding and internalization in macrophages and only a limited consumption of the activity of the human complement system was documented. Conclusions The results clearly indicate the presence of complement proteins on PNPs surface but partially derived from an unspecific deposition rather than an effective complement activation. The presence of a targeting antibody favors the activation of the classical pathway, but its absence allows an increased activation of the alternative pathway. This results in similar opsonization of both PNPs and similar phagocytosis by macrophages, without an impairment of the activity of circulating complement system and, consequently, not enhancing the susceptibility to infection. Graphical abstract

Background: Metastatic pancreatic lesions (MPLs) are relatively uncommon, constituting 2 to 5% of all pancreatic tumors. They often manifest as solitary lesions without distinct clinical symptoms, usually identified incidentally during radiologic imaging for the surveillance of prior malignancies. Differentiating these lesions from primary pancreatic tumors presents a significant challenge due to their nonspecific presentation. Methods: We aimed to prospectively assess the effectiveness of endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration/biopsy (EUS-FNA/B) in diagnosing MPLs in a carefully selected cohort of patients presenting with pancreatic masses. Additionally, we sought to examine the relevance of specific EUS findings in supporting the initial diagnosis of MPLs and their agreement with the definitive cytological diagnosis. This study retrospectively analyzed data from 41 patients diagnosed with MPLs between 2013 and 2023, focusing on their clinical and pathological characteristics, the echogenic features of the pancreatic lesions, and the techniques used for tissue acquisition. Results: The incidence of MPLs in our cohort was 3.53%, with the most frequent primary tumors originating in the kidney (43.90%), colorectum (9.76%), lung (9.76%), lymphoma (9.76%), and breast (4.88%). MPLs typically presented as hypoechoic, oval-shaped lesions with well-defined borders and were predominantly hypervascular. Interestingly, 68.29% of the cases were discovered incidentally during follow-up of the primary tumors, while the involvement of the common bile duct was uncommon (19.51%). Conclusions: EUS and EUS-FNA/B have been validated as valuable diagnostic tools for identifying MPLs. While our findings are promising, further multicenter studies are necessary to corroborate these results and elucidate the predictive value of specific EUS characteristics in determining the metastatic origin of pancreatic lesions.

ObjectiveThe urgent transfer of an intensive care unit (ICU) is particularly challenging because it carries a high clinical and infectious risk and is a critical node in a hospital’s patient flow. In early 2017, exceptional rainfall damaged the roof of the tertiary hospital in Udine, necessitating the relocation of one of the three ICUs for six months. We decided to assess the impact of this transfer on quality of care and patient safety using a set of indicators, primarily considering the incidence of healthcare-associated infections (HAIs) and mortality rates.MethodsWe performed a retrospective, observational analysis of structural, process, and outcome indicators comparing the pre- and posttransfer phases. Specifically, we analyzed data between July 2016 and June 2017 for the transferred ICU and examined mortality and the incidence of HAI.ResultsDespite significant changes in structural and organizational aspects of the unit, no differences in mortality rates or cumulative incidence of HAIs were observed before/after transfer. We collected data for all 393 patients (133 women, 260 men) admitted to the ICU before (49.4%) and after transfer (50.6%). The mortality rate for 100 days in the ICU was 1.90 (34/1791) before and 2.88 (37/1258) after transfer (p = 0.063). The evaluation of the occurrence of at least one HAI included 304 patients (102 women and 202 men), as 89 of them were excluded due to a length of stay in the ICU of less than 48 h; again, there was no statistical difference between the two cumulative incidences (13.1% vs. 6.9%, p = 0.075).ConclusionIn the case studied, no adverse effects on patient outcomes were observed after urgent transfer of the injured ICU. The indicators used in this study may be an initial suggestion for further discussion.

The IC2OC transmission is a continuous transmission whose layout can change from simple IC to simple OC configuration and vice versa. It was proposed to cover a wider range of vehicle speeds without adding gears. Its sizing can lead to higher efficiencies than those of the IC and OC layouts. Therefore, this work deals with the sizing methodologies of this transmission. Two methodologies are proposed and discussed: the first uses the functional and constitutive equations of the transmission; the second is based on a mathematical programming problem. Both methodologies start from the choice of the full mechanical point speeds. The comparison between the two methods is carried out on the transmission of a commercially available 230 kW reach stacker. The comparison shows that the functional method, leaner and faster, can provide results very close to those obtained with the heavy and time-consuming optimization, provided that the values of the two full mechanical point speeds are the optimal ones for the two basic transmissions taken individually.

Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment of hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, that are mainly associated with modest specificity and therapeutic benefit, the three key components that form an ADC (a monoclonal antibody bound to a cytotoxic drug via a chemical linker moiety) achieve remarkable improvement in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tumor toxicity. Based on their beneficial mechanism of action, 15 ADCs have been approved to date by the market approval by the Food and Drug Administration (FDA), the European Medicines Agency (EMA) and/or other international governmental agencies for use in clinical oncology, and hundreds are undergoing evaluation in the preclinical and clinical phases. Here, our aim is to provide a comprehensive overview of the key features revolving around ADC therapeutic strategy including their structural and targeting properties, mechanism of action, the role of the tumor microenvironment and review the approved ADCs in clinical oncology, providing discussion regarding their toxicity profile, clinical manifestations and use in novel combination therapies. Finally, we briefly review ADCs in other pathological contexts and provide key information regarding ADC manufacturing and analytical characterization.

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3′ UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

IntroductionMicroRNAs represent interesting targets for new therapies because their altered expression influences tumor development and progression. miR-17 is a prototype of onco-miRNA, known to be overexpressed in B-cell non-Hodgkin lymphoma (B-NHL) with peculiar clinic-biological features. AntagomiR molecules have been largely studied to repress the regulatory functions of up-regulated onco-miRNAs, but their clinical use is mainly limited by their rapid degradation, kidney elimination and poor cellular uptake when injected as naked oligonucleotides.MethodsTo overcome these problems, we exploited CD20 targeted chitosan nanobubbles (NBs) for a preferential and safe delivery of antagomiR17 to B-NHL cells.ResultsPositively charged 400 nm-sized nanobubbles (NBs) represent a stable and effective nanoplatform for antagomiR encapsulation and specific release into B-NHL cells. NBs rapidly accumulated in tumor microenvironment, but only those conjugated with a targeting system (antiCD20 antibodies) were internalized into B-NHL cells, releasing antagomiR17 in the cytoplasm, both in vitro and in vivo. The result is the down-regulation of miR-17 level and the reduction in tumor burden in a human-mouse B-NHL model, without any documented side effects.DiscussionAnti-CD20 targeted NBs investigated in this study showed physico-chemical and stability properties suitable for antagomiR17 delivery in vivo and represent a useful nanoplatform to address B-cell malignancies or other cancers through the modification of their surface with specific targeting antibodies.

BackgroundCulture-negative periprosthetic joint infections (PJI) are often false diagnosed as aseptic implant failure leading to unnecessary revision surgeries due to repeated infections. A marker to increase the security of e PJI diagnosis is therefore of great importance. The aim of this study was to test C9 immunostaining of periprosthetic tissue as a novel tissue-biomarker for a more reliable identification of PJI, as well as potential cross-reactivity.MethodWe included 98 patients in this study undergoing septic or aseptic revision surgeries. Standard microbiological diagnosis was performed in all cases for classification of patients. Serum parameters including C-reactive protein (CRP) serum levels and white blood cell (WBC) count were included, and the periprosthetic tissue was immunostained for C9 presence. The amount of C9 tissue staining was evaluated in septic versus aseptic tissue and the amount of C9 staining was correlated with the different pathogens causing the infection. To exclude cross-reactions between C9 immunostaining and other inflammatory joint conditions, we included tissue samples of a separate cohort with rheumatoid arthritis, wear particles and chondrocalcinosis.ResultsThe microbiological diagnosis detected PJI in 58 patients; the remaining 40 patients were classified as aseptic. Serum CRP values were significantly increased in the PJI cohort. Serum WBC was not different between septic and aseptic cases. We found a significant increase in C9 immunostaining in the PJI periprosthetic tissue. To test the predictive value of C9 as biomarker for PJI we performed a ROC analyses. According to the Youden’s criteria C9 is a very good biomarker for PJI detection with a sensitivity of 89% and a specificity of 75% and an AUC of 0.84. We did not observe a correlation of C9 staining with the pathogen causing the PJI. However, we observed a cross reactivity with the inflammatory joint disease like rheumatoid arthritis and different metal wear types. In addition, we did not observe a cross reactivity with chondrocalcinosis.ConclusionOur study identifies C9 as a potential tissue-biomarker for the identification of PJI using immunohistological staining of tissue biopsies. The use of C9 staining could help to reduce the number of false negative diagnoses of PJI.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS.