Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, characterized by hyperammonemia and accompanied by a high unmet patient need. mRNA therapies have been shown to be efficacious in hypomorphic Sparse-fur abnormal skin and hair (Spf-ash) mice, a model of late-onset disease. However, studying the efficacy of ornithine transcarbamylase (OTC) mRNA therapy in traditional knockout mice, a model for severe early-onset OTCD, is hampered by the rapid lethality of the model, and poor lipid nanoparticle (LNP) uptake into neonatal mouse liver.

Multidisciplinary high resolution Geophysical Imaging of Pantano Ripa Rossa Segment of the Irpinia Fault (Southern Italy).

The Irpinia Fault, also known as the Monte Marzano Fault System, located in the Southern Apennines (Italy), is one of the most seismically active structures in the Mediterranean. It is the source of the 1980, Ms 6.9, multi-segment rupture earthquake that caused significant damage and nearly 3,000 casualties.

Oncological Outcomes of Open Versus Minimally Invasive Surgery for Ductal Adenocarcinomas of Pancreatic Head: A Propensity Score Matching Analysis.

Background: Minimally invasive pancreatic resections (MIPRs) have been shown to be safe and feasible, but there is still a lack of high-level evidence on oncological outcomes for cephalic pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to compare the oncological outcomes of patients undergoing MIPR and open pancreatic resection (OPR) for pancreatic head cancer in a single high-volume center.

Methods: Data from a prospectively collected database of patients who underwent radical-intent surgery for resectable and borderline resectable PDAC of the head at our institution between January 2013 and May 2023 were retrieved and analyzed, comparing the surgical and oncological outcomes of MIPR and OPR, using a propensity score matching analysis.

Antibiotic-Loaded Hydrogel for the Treatment of Lower-Limb Fracture-Related Infections: A Single Center's Multidisciplinary Experience.

A fracture-related infection (FRI) is a severe complication of an orthopedic trauma, often leading to challenging treatments and poor outcomes. The surgical strategies are typically categorized into one-stage or two-stage procedures, with the use of systemic and local antibiotics being crucial for infection management. This study assessed the efficacy of an antibiotic-loaded hydrogel (ALH) applied over the internal fixation devices for treating FRIs, comparing the outcomes between the one-stage (OS) and two-stage (TS) reconstructions.

Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.

Objective: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.

Design: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.

Recent Advances in Preclinical Studies of the Theranostic Agent [Cu]CuCl.

Cu is gaining recognition not only for its diagnostic capabilities in nuclear medical imaging but also for its therapeutic and theranostic potential. The simultaneous β- and Auger emissions of Cu can be utilized to induce a therapeutic effect on cancerous lesions. The finding of the exceptional biodistribution characteristics of the radionuclide Cu, when administered as basic copper ions, has highlighted its potential therapeutic application in cancer treatment.

Stress-Dependent Optical Extinction in Low-Pressure Chemical Vapor Deposition Silicon Nitride Measured by Nanomechanical Photothermal Sensing.

Understanding optical absorption in silicon nitride is crucial for cutting-edge technologies like photonic integrated circuits, nanomechanical photothermal infrared sensing and spectroscopy, and cavity optomechanics. Yet, the origin of its strong dependence on the film deposition and fabrication process is not fully understood. This Letter leverages nanomechanical photothermal sensing to investigate optical extinction κ at a 632.

Clinical outcomes and survival rates of a uncemented modular revision stem system in hip arthroplasty: a 10-year single-institution study on a frail population.

Introduction: The increasing prevalence of primary hip arthroplasty has led to a parallel rise in revision cases. Femoral revision often entails compromised bone integrity, requiring consideration of various solutions for optimal reconstructive options. Despite technological advancements, there is limited evidence on the clinical outcomes of the latest modular revision stems.

Improved therapeutic efficacy in two mouse models of methylmalonic acidemia (MMA) using a second-generation mRNA therapy.

Isolated methylmalonic acidemia/aciduria (MMA) due to MMUT enzyme deficiency is an ultra-rare pediatric disease with high morbidity and mortality, with no approved disease-altering therapies. Previous publications showed that systemic treatment with a codon-optimized mRNA encoding wild-type human MMUT (MMUT) is a promising strategy for treatment of MMA. We developed a second-generation drug product, mRNA-3705, comprised of an mRNA encoding the MMUT enzyme formulated in a lipid nanoparticle (LNP) with incorporation of enhancements over the previous clinical candidate mRNA-3704.

Cyclotron production of manganese-52: a promising avenue for multimodal PET/MRI imaging.

Background: The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of Mn for PET/MRI imaging.

Results: Using the Cr(p,n)Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating Mn.

Manganese-Loaded Liposomes: An In Vitro Study for Possible Diagnostic Application.

The present study investigates the possible use of manganese (Mn)-based liposomal formulations for diagnostic applications in imaging techniques such as magnetic resonance imaging (MRI), with the aim of overcoming the toxicity limitations associated with the use of free Mn. Specifically, anionic liposomes carrying two model Mn(II)-based compounds, MnCl (MC) and Mn(HMTA) (MH), were prepared and characterised in terms of morphology, size, loading capacity, and in vitro activity. Homogeneous dispersions characterised mainly by unilamellar vesicles were obtained; furthermore, no differences in size and morphology were detected between unloaded and Mn-loaded vesicles.

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study.

Background: Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1).

Lipid Nanoparticle-Mediated Delivery of mRNA Into the Mouse and Human Retina and Other Ocular Tissues.

Purpose: Lipid nanoparticles (LNPs) show promise in their ability to introduce mRNA to drive protein expression in specific cell types of the mammalian eye. Here, we examined the ability of mRNA encapsulated in LNPs with two distinct formulations to drive gene expression in mouse and human retina and other ocular tissues.

Methods: We introduced mRNA-carrying LNPs into two biological systems.

South Tyrol Healthcare Company: A Look at a Peculiar Model of Claims Management in Italy and Analysis of Its Last 11 Years.

Background: Alternative Disputes Resolution (ADR) systems are becoming increasingly important tools in recent years for the management and resolution of health responsibility cases, but their dissemination and efficiency are still poorly described. The purpose of this paper is to present an ADR system in the autonomous province of Bolzano: the Conciliation Commission.

Methods: systematic collection of all claims of the South Tyrol Sanitary Service that were dealt with in the Conciliation Commission from 1 January 2012 to 31 December 2022.

Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria.

Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals.

Mid-Term Outcomes of a Short Modular Neck-Preserving Cementless Hip Stem: A Retrospective Study With a 6-Year Minimum Follow-Up.

Background: The neck-preserving cementless short stem represents a valid therapeutic option for total hip replacement in high-functional-demand patients, but few studies are available about the use of modularity in the last-generation short stem. The aim of the study was to evaluate the mid-term survival of a specific implant design that combines partial collum short hip stem with neck modularity; assessing the functional status was the second endpoint.

Methods: A retrospective single-center cohort study was conducted on 75 patients aged 35 to 80 years, with a minimum 6-year follow-up.

Tc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications.

Background: In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation.

precision-cut liver slices model disease phenotype and monitor therapeutic response for liver monogenic diseases.

Background: In academic research and the pharmaceutical industry, cell lines and animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ.

Regional modulation of toll-like receptor signaling pathway genes in acute epididymitis in mice.

Background: Region-specific immune environments in the epididymis influence the immune responses to uropathogenic Escherichia coli (UPEC) infection, a relevant cause of epididymitis in men. Toll-like receptors (TLRs) are essential to orchestrate immune responses against bacterial infections. The epididymis displays region-specific inflammatory responses to bacterial-derived TLR agonists, such as lipopolysaccharide (LPS; TLR4 agonist) and lipoteichoic acid (LTA; TLR2/TLR6 agonist), suggesting that TLR-associated signaling pathways could influence the magnitude of inflammatory responses in epididymitis.

DNA methylation changes in association with trauma-focused psychotherapy efficacy in treatment-resistant depression patients: a prospective longitudinal study.

: Stressful events increase the risk for treatment-resistant depression (TRD), and trauma-focused psychotherapy can be useful for TRD patients exposed to early life stress (ELS). Epigenetic processes are known to be related to depression and ELS, but there is no evidence of the effects of trauma-focused psychotherapy on methylation alterations.: We performed the first epigenome-wide association study to investigate methylation changes related to trauma-focused psychotherapies effects in TRD patients.