Search Results (748)

Background/Objectives: Modular dual mobility (MDM) cups are constituted by a cobalt-chromium liner inserted into a standard acetabular shell, allowing for intraoperative indication and supplementary screw fixation of the acetabular component. MDM could face mechanical and biological issues, with the associated risk of elevated blood metal ions levels and adverse local tissue reactions. Methods: This is a monocentric retrospective study on a consecutive series of 105 patients who underwent primary unilateral THA with the G7 Dual Mobility Acetabular System cup (Zimmer Biomet, Warsaw, IN, USA) from March 2019 to April 2023, and who were evaluated clinically and radiographically at a minimum two-year follow-up. All complications and revisions were recorded. Survivorship analysis with any revision surgery as endpoint was performed using Kaplan–Meier survival curves. Results: There were eighty-nine patients (follow-up rate 84.8%) who underwent clinical and radiographic follow-up. The mean follow-up was 2.5 ± 0.8 years. Revision-free survival was 98.0%. Three complications (2.8%) were recorded: one case of posterior dislocation, one periprosthetic joint infection and one post-traumatic periprosthetic femur fracture. Dislocation rate and infection rate were less than 1.0%. None of the patients were revised for adverse local tissue reactions. No cup loosening was observed. No cases of intraprosthetic dislocation, liner malseating or femoral notching were observed. Retroacetabular stress shielding was present in 43.0% of patients. Clinical scores significantly improved at the last follow-up compared with preoperative status (p < 0.0001): the final mean mHHS was 87.5 ± 5.3 and the final mean VAS was 0.5 ± 0.9. Conclusions: The Zimmer G7 modular dual mobility cup appears to be a safe and effective option and does not present specific implant-related mechanical and biological issues in primary total hip arthroplasty at a minimum two-year follow-up. Full article

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2–p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC₅₀ 6.67–8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (−10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski’s Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile. Full article

Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC. Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins. Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation. Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC. Full article

The accurate segmentation of multiple sclerosis (MS) lesions in magnetic resonance imaging (MRI) is essential for diagnosis, disease monitoring, and therapeutic assessment. Despite the significant advances in deep learning-based segmentation, the current boundary-aware approaches are limited by their reliance on spatial distance transforms, which fail to fully exploit the rich texture and intensity information inherent in MRI data. This limitation is particularly problematic in regions where MS lesions and normal-appearing white matter exhibit overlapping intensity distributions, resulting in ambiguous boundaries and reduced segmentation accuracy. To address these challenges, we propose a novel Mahalanobis distance map (MDM) and a corresponding Mahalanobis distance loss, which generalize traditional distance transforms by incorporating spatial coordinates, the FLAIR intensity, and radiomic texture features into a unified feature space. Our method leverages the covariance structure of these features to better distinguish ambiguous regions near lesion boundaries, mimicking the texture-aware reasoning of expert radiologists. Experimental evaluation on the ISBI-MS and MSSEG datasets demonstrates that our approach achieves superior performance in both boundary quality metrics (HD95, ASSD) and overall segmentation accuracy (Dice score, precision) compared to state-of-the-art methods. These results highlight the potential of texture-integrated distance metrics to overcome MS lesion segmentation difficulties, providing more reliable and reproducible assessments for MS management and research. Full article

Chimeric compounds represent a promising strategy in cancer therapy by simultaneously targeting multiple pathways responsible for tumour growth and survival. Their structure comprises two or more pharmacophores connected through suitable chemical linker. These dual or multi-functional drugs can interact with several biological targets for a more pronounced pharmacological effect. In order to identify new multi-targeting agents with anticancer efficacy, we designed and synthesised a series of novel multi-functional molecules by covalently linking antitumor compounds dichloroacetate (DCA) and Nutlin-3a. The design was aimed at addressing two critical events in cancer: (1) the Warburg effect and (2) the dysregulations of protein p53 pathway, both of which are directly linked to the predominant survival and aggressive proliferation of malignant cells. DCA reactivate oxidative phosphorylation by inhibiting mitochondria pyruvate dehydrogenase kinase (PDK), thereby unlocking the Warburg metabolism of cancer cells and its antiapoptosis state. Concurrently, Nutlin-3a restores the protective function of the “genome guardian” p53 protein, by blocking its antagonist oncoprotein E3 ligase MDM2. Chimeric compounds were obtained using a chemoenzymatic multi-step procedure that included a key lipase-catalysed asymmetric reaction. Biological evaluation of the synthesised Nutlin-DCA chimeras in a panel of three cancer cell lines demonstrated promising results in vitro. Specifically, compounds rac-19a, rac-19b, rac-20a, rac-20b and enantioenriched 20a caused a statistically significant reduction in cell viability at micromolar concentrations. These findings suggest that targeting both the Warburg effect and the p53 pathway with a single molecule is a viable approach for future cancer therapeutic development. Full article

Proteolysis-targeting chimeras (PROTACs) are a transformative therapeutic modality that co-opts the ubiquitin-proteasome system for selective protein degradation. To date, the development of PROTACs has been overwhelmingly dominated by the recruitment of four canonical E3 ligases: CRBN, VHL, MDM2, and IAP. This limited repertoire represents a critical bottleneck, restricting the scope of degradable proteins and potential therapeutic applications. Addressing this challenge, recent years have witnessed a surge in the successful recruitment of novel E3 ligases. This review provides a dedicated and comprehensive summary of this progress, focusing exclusively on the emerging E3 ligases and their cognate ligands reported for PROTAC technology outside of the well-established quartet. We detail their discovery and strategic application, highlighting how this rapidly expanding toolbox promises to overcome existing limitations and unlock the full potential of targeted protein degradation. Full article

Emotion recognition from electroencephalography (EEG) often relies on Euclidean features that ignore the curved geometry of covariance matrices. We introduce a Riemannian-manifold pipeline which, combined with the Fisher Geodesic Minimum Distance to Mean (FgMDM) classifier, leverages the full geometry of symmetric positive-definite (SPD) EEG covariances. The approach applies an additional geodesic-mean contraction that stabilizes trial covariances before tangent space projection. Experiments on the five-class SEED-V dataset show high accuracy, robustness to session-to-session variability and improved interpretability relative to baselines. These results highlight Riemannian geometry as a powerful framework for emotion recognition with high-dimensional, non-stationary EEG. Full article

Background/Objectives: Microglia are the primary immune cells in the central nervous system (CNS) and are known as “resident” macrophages. The aim of this study was to determine the effect of acute ethanol (EtOH) on the microglia state and monocyte infiltration into the CNS, with particular attention to the role of peripheral and central dopamine (DA) D2 receptors (D2Rs) in mediating EtOH effects on peripheral and central substrates. We hypothesize that EtOH interacts with peripheral immune mediators via D2Rs including monocyte-derived macrophages (MDMs) to modulate midbrain neurons, DA transmission in the mesolimbic pathway from the ventral tegmental area (VTA) to nucleus accumbens (NAc), and the intoxicating effects of acute EtOH. Methods: Using the Macrophage FAS-Induced Apoptosis (MaFIA) mouse model (GFP+ on Csf1r promoter), we assessed the effects of three intraperitoneal (IP) doses of EtOH (1, 2, and 4 g/kg) at three time points (0.5, 1, and 2 h after injection) on D2R expression in blood leukocytes and microglia, as well as midbrain neuronal activity, DA release, and behavior. Results: Acute EtOH significantly enhanced lymphocyte and monocyte D2R expression at 1.0 g/kg by 2 h after injection in vivo but decreased D2R expression in vitro. Ethanol enhanced microglia D2R expression in the NAc, while not altering D2R expression in the VTA, but altered the microglia state in these areas, shifting them toward an inflammatory phenotype. Acute EtOH induced prolonged and progressive hypersensitivity of D2R activation of VTA GABA neurons. Intravenous injection of the macrophage depleter liposomal clodronate significantly reduced blood macrophages by 55.3% and blocked the typical inhibition of VTA GABA neurons by EtOH, as well as the enhancement of DA levels in the NAc, and the locomotor indices of intoxication produced by acute EtOH, but not choice place preference. Conclusions: These findings strongly suggest a neuroimmune peripheral connection for acute low-dose EtOH use and challenge the dogma that central actions of EtOH exclusively mediate its effect on DA neuronal activity and release. Full article

Background/Objectives: Donkey milk (DM) has been considered a valuable alternative to human and bovine counterparts as well as to infant formulas. Milk extracellular vesicles (EVs) have been proposed to influence key biological processes. The purpose of this study is to provide a comprehensive characterization of the protein composition of extracellular vesicles (EVs) by extending quantitative proteomic comparisons to EVs derived from donkey colostrum (DC) and mature donkey milk (MDM). Methods: The EVs were isolated from DC and MDM samples, characterized, and subjected to proteomic analysis using the tandem mass tag-based quantitative approach. Results: In addition to typical milk proteins and EV markers, EVs from DC and MDM both contain components associated with the immune system, immune response, or promoting tissue repair, and assisting with communication between the infant and their environment. The EVs from DC were enriched in proteins associated with protein turnover, specific defense functions, and regenerative processes. Conclusions: Overall, the results can contribute to the broader characterization of the overall protein composition of DC and MDM and might help to predict the beneficial effects of the corresponding EVs on various mammalian cells. They may also provide valuable insights for the development of novel DM-based products for food, pharmaceutical, and biotechnological applications. Full article

While Moringa oleifera Lam. (MO) extracts are known to have various bioactive properties, including anti-inflammatory properties, the components responsible still remain to be identified. This study explores the protective effects of the MO component, 7-octenoic acid (7OCT) in LPS-stimulated THP-1 macrophage inflammatory responses. The compound significantly downregulated the production of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, as well as the expression of inflammation-related genes NFKB1, PTGS2, and NOS2. Additionally, it inhibited the nuclear translocation of NF-κB p65, a key transcription factor of inflammatory signaling cascade. Effects on oxidative stress showed that 7OCT inhibited LPS-induced NADPH oxidase 2 (NOX2) component genes including CYBB, CYBA, NCF1, NCF2, and NFE2L2, along with phosphorylated NOX2 and p47^phox proteins. The compound reduced the expression of TP53, BAX, CASP3, and CASP7, while enhancing BCL2 expression and Bcl-2 protein levels, suggesting an effect on apoptosis. Decreased levels of BAX, caspase-3, and cleaved caspase-3 proteins further confirmed its anti-apoptotic effect. Our findings suggest that 7OCT exhibits strong anti-inflammatory, antioxidant, and anti-apoptotic properties. Full article

The study aim was to apply murine double minute 2 (MDM2)-siRNA to a biodegradable siRNA delivery vector, ternary complex, for treating colorectal cancer peritoneal dissemination. The ternary complex containing MDM2-siRNA (MDM2-siRNA complex) was constructed by mixing MDM2-siRNA, dendrigraft poly-L-lysine, and γ-polyglutamic acid. Cellular uptake of the ternary complex and suppressive effect on MDM2-mRNA were determined in a mouse colorectal cancer cell line. Tumor-growth inhibition by the MDM2-siRNA complex was evaluated in peritoneal dissemination model mice. The MDM2-siRNA complex, with an approximately 177 nm particle size and −35 mV ζ-potential, prevented degradation of the inner siRNA by RNase. In the in vitro study, the ternary complex was highly taken up by the cells, and 2 μg/mL of the MDM2-siRNA complex significantly decreased MDM2-mRNA to about 30% of control cells. Intraperitoneal administration in colorectal cancer peritoneal dissemination model mice showed little effect of the ternary complex containing scramble-siRNA on cancer growth in the peritoneal cavity. Conversely, the MDM2-siRNA complex significantly reduced peritoneal dissemination to less than 1/1000th of control mice and successfully prolonged survival time. In this study, we found that the biodegradable MDM2-siRNA complex had a suppressive effect on MDM2-mRNA in cancer cells and tumor growth of peritoneal dissemination. Full article

Acute lymphoblastic leukemia (ALL) remains a formidable therapeutic challenge, particularly within high-risk cohorts. Advances in next-generation sequencing have elucidated critical mutations that significantly influence prognosis and therapeutic decision-making. Tyrosine kinase inhibitors (TKIs) have significantly improved treatment outcomes in Philadelphia chromosome-positive (Ph+) ALL. Meanwhile, emerging therapies such as monoclonal antibodies and chimeric antigen receptor (CAR) T-cell therapies show promise for B-cell ALL, although they are associated with considerable toxicities. These developments underscore the persistent need for alternative therapeutic strategies that can benefit a wider range of patients. In this study, human ALL cell lines—characterized by either wild-type or mutant tumor protein p53 (TP53) status—were treated with RG7388 (an MDM2 (mouse double minute 2 homolog) inhibitor) and BBI608 (a STAT3 (signal transducer and activator of transcription 3) inhibitor), both as single agents and in combination. Cell viability was quantified using XTT assays, while apoptosis was assessed via flow cytometry. Additionally, immunoblotting and qRT-PCR were employed to evaluate changes in protein and gene expression, respectively. RG7388 demonstrated potent growth inhibition in the majority of ALL cell lines, with p53-mutant cell lines exhibiting resistance. BBI608 reduced cell viability across all tested cell lines, though with variable sensitivity. Notably, the combination of RG7388 and BBI608 elicited synergistic anti-proliferative effects in p53 wild-type and partially functional p53-mutant cells, enhancing apoptosis and stabilizing p53 protein levels. In contrast, MOLT-4 cells, which harbor concurrent TP53 and STAT3 mutations, did not benefit from the combination treatment, indicating an inherent resistance phenotype within this subset. Collectively, these findings highlight the therapeutic potential of combined MDM2 and STAT3 inhibition in ALL, particularly in p53 wild-type and partially functional p53-mutant contexts. This combinatorial approach augments apoptosis and tumor growth suppression, offering a promising avenue for expanding treatment options for a broader patient population. Further investigation is warranted to validate these preclinical findings and to explore translational implications in genetically diverse ALL subsets. Full article

Baboons’ management requires chemical restraint. Three intramuscular sedative protocols in captive hamadryas baboons (Papio hamadryas) undergoing health-check and male vasectomy were compared. Animals were assigned to TZD_G (n = 17; tiletamine/zolazepam 3 mg/kg + dexmedetomidine 20 μg/kg), KDM_G (n = 23; ketamine 6 mg/kg + dexmedetomidine 30 μg/kg + methadone 0.2 mg/kg), or MDM_G (n = 9; midazolam 2 mg/kg + dexmedetomidine 60 μg/kg + methadone 0.2 mg/kg). Propofol was titrated intravenously for anaesthetic induction and maintenance. Sedation time and quality and cardiopulmonary parameters were recorded. Atipamezole (TZD_G 0.2 mg/kg, KDM_G 0.3 mg/kg, MDM_G 0.6 mg/kg) and flumazenil (MDM_G 0.02 mg/kg) were administered intramuscularly post-procedure. Recovery time and quality were recorded. Data were reported as median (interquartile range) or regression coefficient (B). Sedation was deepest in TZD_G (20, 20–20; KDM_G 20, 19–20; MDM_G 19, 15–20; p = 0.017). MDM_G had a significantly higher heart rate (B = 10.27, p = 0.001), respiratory rate (B = 9.09, p < 0.001), and lower end-tidal carbon dioxide (B = −3.00, p = 0.03) than TZD_G, while KDM_G had a lower respiratory rate than TZD_G (B = −3.67, p = 0.02) and a higher temperature (B = 1.66 p = 0.001). TZD_G showed the longest recovery (minutes: 19, 11.5–30; KDM_G: 6, 4–12; MDM_G: 4, 2.5–5; p < 0.001), while MDM_G the best recovery (0, 0–0; TZD_G: 9, 6–12; KDM_G: 0, 0–6; p < 0.001). TZD produced deepest sedation but bad recovery; KDM offered optimal sedation and recovery, and cardiopulmonary stability; MDM provided lighter sedation and excellent recovery. Full article

The symbiotic microbiome constitutes a consortium that has been persistently domesticated by a specific algal species, fostering a close and enduring association with the host. The majority of microbial taxa remain uncharacterized. These unknown microbes, often referred to as “microbial dark matter (MDM)”, have important ecological contributions. Given the challenges in discerning symbiotic microbes in natural environments, herein, ecological characteristics of MDM and known taxa within symbiotic communities were investigated in a simulated bloom process using Alexandrium pacificum without antibiotic treatment. Specifically, increased diversification was observed in MDM along the bloom process. Higher trophic interaction and less vulnerability of the molecular network were found in MDM taxa. The “bridge” role of MDM species was better than that of known taxa, as shown by higher betweenness centralization. Deterministic processes dominated in MDM taxa, which promote phylogenic diversity of such groups to some extent. The findings highlight that MDM taxa play an important role in sustaining community stability and functioning. This study broadens our understanding of the ecological contribution of MDM under disturbances from dinoflagellate blooms, providing essential theoretical insights and empirical data to inform the management of coastal toxic blooms. Full article

In this paper, we design a new type of terahertz orbital angular momentum (OAM) optical fiber with excellent transmission characteristics over a wide frequency range. Within the 0.8–1.8 THz frequency band, it shows stable support for transmission of the fifth-order OAM mode. Its dispersion control effect is excellent; it maintains the confinement loss of most modes at the extremely low level of 10⁻¹⁰ dB/m; its maximum dispersion is only 5.57 ps/THz/cm; and its effective mode field area is greater than 1.11 × 10⁻⁷ m². These characteristics jointly endow this optical fiber with broad application prospects and significant research value in the field of terahertz communication. With the continuous advancement of technology in this field, this optical fiber is expected to become a key component when building efficient, reliable, and large-capacity communication systems. Full article