Search Results (21)

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation. Full article

This study aims to retrospectively assess the safety of [²²⁵Ac]Ac-PSMA-PRLT, both as monotherapy and in combination (TANDEM) with Lutetium-177, concerning tolerance after the radiopharmaceutical administration and long-term safety, its impact on salivary glands’ function, overall survival (OS), and follow-up duration. Between December 2020 and September 2024, 89 patients received a total of 151 cycles of [²²⁵Ac]Ac-PSMA-PRLT. Patients with at least one follow-up (n = 71) were included in the analysis to evaluate xerostomia, as well as long-term hematological, renal, and hepatic toxicities, graded according to CTCAE v5.0. The most common adverse event after the radiopharmaceutical administration was flare pain (n = 16). As of the time of analysis, 68 patients had passed away (76.4%; range of survival 5 days to 39 months, median 7 months), while 21 patients were still alive (23.6%; follow-up duration: 1–33 months). Severe (G3/G4) long-term adverse events were rare, with 15 cases of G3 anemia (21.1%), 6 cases of G3 leukocytopenia (8.4%), and 14 cases of G3/G4 thrombocytopenia (19.7%). Hematological toxicity was primarily associated with severe bone marrow involvement or prior chemotherapy. Additionally, one case of G3 nephrotoxicity (1.4%) and six cases of G3 hepatotoxicity (8.4%) were observed. Only nine patients (12.7%) reported de novo xerostomia (G1/G2). In conclusion, this study demonstrates that [²²⁵Ac]Ac-PSMA PRLT, both as monotherapy and combined with [¹⁷⁷Lu]Lu-PSMA as TANDEM PRLT, is generally safe in terms of both tolerance after the radiopharmaceutical administration and long-term toxicity. Full article

Cannabis-based medicines (CBMs) could help reduce systemic inflammation in people with HIV (PWH). In a prospective, randomized pilot study we enrolled participants from August 2021–April 2022 with HIV, aged ≥18 and on antiretroviral therapy and randomly assigned them to cannabidiol (CBD) ± Δ9-tetrahydrocannabinol (THC) capsules for 12 weeks with the primary objective being to assess safety and tolerability. Here we report on timeliness to study initiation, enrolment, compliance and retention rates. The target sample size was not reached. Two hundred and five individuals were approached, and 10 consented and were randomized; the rest refused (reasons: cannabis-related stigma/discomfort; too many study visits/insufficient time; unwillingness to undergo a “washout period” for three weeks) or were not eligible. The age of those randomized was 58 years (IQR 55–62); 80% were male. Only three met all criteria (30% enrolment compliance); seven were enrolled with minor protocol deviations. Compliance was excellent (100%). Eight (80%) participants completed the study; two (20%) were withdrawn for safety reasons (transaminitis and aggravation of pre-existing anemia). Time to study initiation and recruitment were the most challenging aspects. Ongoing work is required to reduce stigma related to CBMs. Future studies should find a balance between the requirements for safety monitoring and frequency of study visits. Full article

Low levels of delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) values are indicative of cartilage degeneration. Patients with early rheumatoid arthritis are known to have low dGEMRIC values due to inflammatory activity. The additional effect of biological disease-modifying antirheumatic drug (bDMARD) and conventional synthetic disease-modifying antirheumatic drug (csDMARD) treatment on cartilage status is still unclear. In this prospective, double-blinded, randomized proof-of-concept clinical trial, patients with early rheumatoid arthritis (disease duration less than 12 months from symptoms onset) were treated with methotrexate + adalimumab (10 patients: 6/4 (f/m)). A control group with methotrexate alone (four patients: 2/2 (f/m)) was used. Cartilage integrity in the metacarpophalangeal joints was compared using dGEMRIC at baseline, 12, and 24 weeks after treatment initiation. A statistically significant increase in dGEMRIC levels was found in the adalimumab group considering the results after 12 and 24 weeks of therapy (p < 0.05) but not in the control group (p: non-significant). After 24 weeks, a tendency towards increased dGEMRIC values under combination therapy was observed, whereas methotrexate alone showed a slight decrease without meeting the criteria of significance (dGEMRIC mean change: +85.8 ms [−156.2–+346.5 ms] vs. 30.75 ms [−273.0–+131.0 ms]; p: non-significant). After 24 weeks of treatment with a combination of methotrexate and adalimumab, a trend indicating improvement in cartilage composition is seen in patients with early rheumatoid arthritis. However, treatment with methotrexate alone showed no change in cartilage composition, as observed in dGEMRIC sequences of metacarpophalangeal joints. Full article

The occurrence of Cr (VI) in drinking water resources in low but toxicologically relevant concentrations requires the development of reliable and industrially applicable separation processes in drinking water treatment. There is little information in the literature on the removal of chromium species at concentrations below 10 µg/L. Therefore, in this study, the removal of chromium in the concentration range ≤10 µg/L was investigated using three separation processes, activated carbon filtration (ACF), reduction/coagulation/filtration (RCF) and low-pressure reverse osmosis (LPRO), in both laboratory- and pilot-scale tests. In ACF treatment, Cr (III) was removed by deep bed filtration over 1.5 m of anthracite at a pH of 7.5 (which was used as a prefilter prior to ACF), while Cr (VI) was removed up to 75% via ACF at a filter bed depth of 2.5 m. Fresh activated carbon (AC) exhibited the highest adsorption capacity for Cr (VI), while reactivated AC had a significantly lower capacity for Cr (VI), which was attributed to calcium and iron deposits. In technical filters, where multiple reactivated activated carbon is used, this led to a low removal rate for Cr (VI). Using the RCF process with Fe (II) dosing in a continuous flow reactor at a specific coagulant dosing ratio, high Cr (VI) removal, down to a concentration of 0.1 µg/L, was achieved within minutes. The subsequent anthracite filtration ensured the complete removal of Fe (III) and Cr (III) precipitates. The RCF process was limited by the oxygen side reaction with Fe (II), which dominated at Cr (VI) concentrations below 1 µg/L. In addition, a four-step LPRO process with concentrate recycling showed effective removal (>99%) of both Cr (III) and Cr (VI) species in raw water as well as a negligible effect of pH in the testing pH range of 5.6 to 8.3 on the Cr (VI) removal. Nevertheless, the water hardness and pH of the LPRO permeate must be increased to make it available as drinking water. The three separation processes were found to be able to meet the expected more stringent future regulations for Cr (VI) level in drinking water. The most suitable technology, however, can be selected with respect to the raw water quality/characteristics, site-specific conditions and the already existing equipment. Full article

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients. Full article

Our goal was to create bioimitated scaffolding materials for biomedical purposes. The guiding idea was that we used an interpenetrating structural hierarchy of natural extracellular matrix as a “pattern” to design hydrogel scaffolds that show favorable properties for tissue regeneration. Polymeric hydrogel scaffolds are made in a simple, environmentally friendly way without additional functionalization. Gelatin and 2-hydroxyethyl methacrylate were selected to prepare interpenetrating polymeric networks and linear alginate chains were added as an interpenetrant to study their influence on the scaffold’s functionalities. Cryogelation and porogenation methods were used to obtain the designed scaffolding biomaterials. The scaffold’s structural, morphological, and mechanical properties, in vitro degradation, and cell viability properties were assessed to study the effects of the preparation method and alginate loading. Apatite as an inorganic agent was incorporated into cryogelated scaffolds to perform an extensive biological assay. Cryogelated scaffolds possess superior functionalities essential for tissue regeneration: fully hydrophilicity, degradability and mechanical features (2.08–9.75 MPa), and an optimal LDH activity. Furthermore, cryogelated scaffolds loaded with apatite showed good cell adhesion capacity, biocompatibility, and non-toxic behavior. All scaffolds performed equally in terms of metabolic activity and osteoconductivity. Cryogelated scaffolds with/without HAp could represent a new advance to promote osteoconductivity and enhance hard tissue repair. The obtained series of scaffolding biomaterials described here can provide a wide range of potential applications in the area of biomedical engineering. Full article

New composite 3D scaffolds were developed as a combination of synthetic polymer, poly(2-hydroxyethyl methacrylate) (PHEMA), and a natural polymer, gelatin, with a ceramic component, nanohydroxyapatite (ID nHAp) dopped with metal ions. The combination of a synthetic polymer, to be able to tune the structure and the physicochemical and mechanical properties, and a natural polymer, to ensure the specific biological functions of the scaffold, with inorganic filler was applied. The goal was to make a new material with superior properties for applications in the biomedical field which mimics as closely as possible the native bone extracellular matrix (ECM). Biodegradable PHEMA hydrogel was obtained by crosslinking HEMA by poly(β-amino esters) (PBAE). The scaffold’s physicochemical and mechanical properties, in vitro degradation, and biological activity were assessed so to study the effects of the incorporation of nHAp in the (PHEMA/PBAE/gelatin) hydrogel, as well as the effect of the different pore-forming methods. Cryogels had higher elasticity, swelling, porosity, and percent of mass loss during degradation than the samples obtained by porogenation. The composite scaffolds had a higher mechanical strength, 10.14 MPa for the porogenated samples and 5.87 MPa for the cryogels, but a slightly lower degree of swelling, percent of mass loss, and porosity than the hybrid ones. All the scaffolds were nontoxic and had a high cell adhesion rate, which was 15–20% higher in the composite samples. Cell metabolic activity after 2 and 7 days of culture was higher in the composites, although not statistically different. After 28 days, cell metabolic activity was similar in all scaffolds and the TCP control. No effect of integrating nHAp into the scaffolds on osteogenic cell differentiation could be observed. Synergetic effects occurred which influenced the mechanical behavior, structure, physicochemical properties, and interactions with biological species. Full article

The spread by arthropods (zoochory) is an essential dispersal mechanism for many microorganisms, like plant pathogens. Carabid beetles are very abundant and mobile ground-dwelling insects. However, their role in the dispersal of economically relevant phytopathogens, like Fusarium and Alternaria fungi is basically unknown. We quantified the total fungal, Fusarium, and Alternaria load of carabid species collected in the transition zones between small water bodies and wheat fields by screening (i) their body surface for fungal propagules with a culture-dependent method and (ii) their entire bodies for fungal DNA with a qPCR approach. The analysis of entire bodies detects fungal DNA in all carabid beetles but Alternaria DNA in 98% of them. We found that 74% of the carabids carried fungal propagules on the body surface, of which only half (49%) carried Fusarium propagules. We identified eight Fusarium and four Alternaria species on the body surface; F. culmorum was dominant. The fungal, Fusarium and Alternaria, load differed significantly between the carabid species and was positively affected by the body size and weight of the carabids. Carabid beetles reveal a remarkable potential to disseminate different fungi. Dispersal by ground-dwelling arthropods could affect the spatial-temporal patterns of plant disease and microorganisms in general. Full article

Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation. Full article

The field of tissue engineering has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes for regenerative medicine and pharmaceutical research. Conventional scaffold-based approaches are limited in their capacity to produce constructs with the functionality and complexity of native tissue. Three-dimensional (3D) bioprinting offers exciting prospects for scaffolds fabrication, as it allows precise placement of cells, biochemical factors, and biomaterials in a layer-by-layer process. Compared with traditional scaffold fabrication approaches, 3D bioprinting is better to mimic the complex microstructures of biological tissues and accurately control the distribution of cells. Here, we describe recent technological advances in bio-fabrication focusing on 3D bioprinting processes for tissue engineering from data processing to bioprinting, mainly inkjet, laser, and extrusion-based technique. We then review the associated bioink formulation for 3D bioprinting of human tissues, including biomaterials, cells, and growth factors selection. The key bioink properties for successful bioprinting of human tissue were summarized. After bioprinting, the cells are generally devoid of any exposure to fluid mechanical cues, such as fluid shear stress, tension, and compression, which are crucial for tissue development and function in health and disease. The bioreactor can serve as a simulator to aid in the development of engineering human tissues from in vitro maturation of 3D cell-laden scaffolds. We then describe some of the most common bioreactors found in the engineering of several functional tissues, such as bone, cartilage, and cardiovascular applications. In the end, we conclude with a brief insight into present limitations and future developments on the application of 3D bioprinting and bioreactor systems for engineering human tissue. Full article

Simulating diaphyseal fracture healing via numerical models has been investigated for a long time. It is apparent from in vivo studies that metaphyseal fracture healing should follow similar biomechanical rules although the speed and healing pattern might differ. To investigate this hypothesis, a pre-existing, well-established diaphyseal fracture healing model was extended to study metaphyseal bone healing. Clinical data of distal radius fractures were compared to corresponding geometrically patient-specific fracture healing simulations. The numerical model, was able to predict a realistic fracture healing process in a wide variety of radius geometries. Endochondral and mainly intramembranous ossification was predicted in the fractured area without callus formation. The model, therefore, appears appropriate to study metaphyseal bone healing under differing mechanical conditions and metaphyseal fractures in different bones and fracture types. Nevertheless, the outlined model was conducted in a simplified rotational symmetric case. Further studies may extend the model to a three-dimensional representation to investigate complex fracture shapes. This will help to optimize clinical treatments of radial fractures, medical implant design and foster biomechanical research in metaphyseal fracture healing. Full article

In response to increasingly stringent restrictions for drinking water quality, a parallel operation of two common technologies, low-pressure reverse osmosis (LPRO) and activated carbon filtration (ACF), was investigated in a comprehensive five-month pilot study for the removal of 32 typical trace organic contaminants (TrOCs) from Rhine bank filtrates employing a semi- technical plant. TrOCs have been divided into three groups: polyfluorinated aliphatic compounds; pharmaceuticals, pesticides and metabolites; in addition to volatiles, nitrosamines and aminopolycarboxylic acids, which were also examined. The net pressure behavior, normalized salt passage and rejection of TrOCs by LPRO were investigated and compared with ACF operation. In addition, autopsies from the leading and last membrane modules were performed using adenosine triphosphate (ATP), total organic carbon (TOC), ICP-OES and SEM-EDX techniques. Generally, rather stable LPRO membrane performance with limited membrane fouling was observed. TrOCs with a molecular weight of ≥ 150 Da were completely retained by LPRO, while the rejection of di- and trichloro compounds improved as the filtration progressed. ACF also showed significant removal for most of the TrOCs, but without desalination. Accordingly, the ACF and LPRO can be operated in parallel such that the LPRO permeate and the ACF-treated bypass can be mixed to produce drinking water with adjustable hardness and significantly reduced TrOCs. Full article

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies. Full article

The Karlsruhe Tritium Neutrino (KATRIN) experiment aims at measuring the effective electron neutrino mass with a sensitivity of 0.2 eV/c², i.e., improving on previous measurements by an order of magnitude. Neutrino mass data taking with KATRIN commenced in early 2019, and after only a few weeks of data recording, analysis of these data showed the success of KATRIN, improving on the known neutrino mass limit by a factor of about two. This success very much could be ascribed to the fact that most of the system components met, or even surpassed, the required specifications during long-term operation. Here, we report on the performance of the laser Raman (LARA) monitoring system which provides continuous high-precision information on the gas composition injected into the experiment’s windowless gaseous tritium source (WGTS), specifically on its isotopic purity of tritium—one of the key parameters required in the derivation of the electron neutrino mass. The concentrations c_x for all six hydrogen isotopologues were monitored simultaneously, with a measurement precision for individual components of the order 10⁻³ or better throughout the complete KATRIN data taking campaigns to date. From these, the tritium purity, ε_T, is derived with precision of <10⁻³ and trueness of <3 × 10⁻³, being within and surpassing the actual requirements for KATRIN, respectively. Full article