Search Results (1,564)

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

Microplastics (MPs) can serve as bearers of microorganisms and additional contaminants. However, the functional composition and assembly processes of plastisphere bacteria in co-contaminated soil–plant systems are not yet well understood. Using a pot experiment, we examined the effects of both individual and combined cadmium (Cd) and polypropylene (PP) MP contamination on the development of the bioenergy plant sorghum. The bacterial community, co-occurrence networks, and assembly processes in the rhizosphere soil and PP plastisphere were investigated using high-throughput sequencing. Compared with contamination by a single compound, combined contamination with Cd and PP had a more potent inhibitory effect on the development of sorghum. PCoA and diversity indices indicate that the bacterial community on PP plastics is structurally simpler than that in rhizosphere soil. The PP plastisphere could recruit bacteria from the genera Sphingomonas, Rhizobium, and Bacillus. The bacterial communities in the soil and the PP plastisphere were mostly formed by stochastic processes, with diffusion limitation playing a greater role in the bacterial community in the PP plastisphere. Co-occurrence network analysis revealed differences between the bacterial communities in the soil and in the PP plastisphere, with the network in the PP plastisphere showing lower complexity and connectivity. Functional prediction revealed that the prevalence of nitrogen cycling genes was greater in the PP plastisphere than in the dirt and that the PP plastisphere presented greater metabolic activity. The relative prevalence of metabolic pathways associated with human diseases was markedly elevated in the PP plastisphere, which may be correlated with the dissemination of pathogenic microorganisms. These findings indicate that the PP plastisphere, as a distinct microbial niche, might attract certain bacteria, consequently affecting the functional characteristics of cocontaminated soil–plant systems. Full article

The South Sakhalin mud volcano (Sakhalin Island, Russia) emits HCO₃-Cl/Na-Mg water, emanates CO₂ prevailing over CH₄ in the gas phase, and extrudes mud bearing five carbonate mineral species. The study focuses on the distribution, diversity, and origin of the carbonate minerals from the mud volcano (MV) ejecta, in terms of carbon cycle processes. The data presented include a synthesis of field observations, compositions of MV gases and waters, chemistry of carbonate minerals, as well as stable isotope geochemistry of MV waters (δ¹³C, δD, and δ¹⁸O) and carbonates (δ¹³C and δ¹⁸O). The sampled MV waters are isotopically heavy, with δ¹⁸O = +5.7‰ to +7.5‰ VSMOW, δD = −18.0‰ to −11.0‰ VSMOW, and ¹³C (δ¹³C_DIC = +6.9‰ to +8.1‰ VPDB). This composition may be due to the dilution of basinal water with dehydration water released during the diagenetic illitization of smectite. Carbonates in the sampled mud masses belong to three genetically different groups. Mg-rich siderite, (Fe_0.54–0.81Mg_0.04–0.30Ca_0.05–0.23Mn_0.00–0.08)CO₃, disseminated in abundance throughout the mud masses, coexists with common calcite and sporadic ankerite. The trace-element chemistry of Mg-siderite, as well as the oxygen (δ¹⁸O = +34.4‰ to +36.8‰ VSMOW) and carbon (δ¹³C = −1.3‰ to +0.6‰ VPDB) isotopic signatures, confirms its authigenic origin. Siderite formed during early diagenesis of the Upper Cretaceous sandy and clayey marine sediments mobilized by mud volcanism in the area. Another assemblage, composed of dawsonite, siderite, and vein calcite (±kaolinite), represents altered arkose sandstones found as few fragments in the mud. This assemblage may be a marker of later CO₂ flooding into the sandstone aquifer in the geological past. The trace-element chemistry, particular morphology, and heavy C (δ¹³C = +5.5‰ to +7.0‰ VPDB) and O (δ¹⁸O = +39.1‰ to +39.5‰ VSMOW) isotope compositions indicate that aragonite is the only carbonate species that is related to the current MV activity. It crystallized in a shallow reservoir and was maintained by CO₂ released from rapidly ascending liquefied mud and HCO₃-Cl/Na-Mg-type of MV waters. Full article

Chlamydia trachomatis has a significant impact on public health, especially among adolescents and young women; it primarily affects urogenital epithelial cells, leading to cervicitis and urethritis, with >90% of cases showing no symptoms. Consequently, chlamydial infections are commonly misdiagnosed, and, if untreated, they may result in severe reproductive sequelae including infertility. A better understanding of C. trachomatis cell biology and bacterial–host cell interactions may be helpful to identify strategies able to counter its transmission among the population, as well as its dissemination in reproductive tissues, reducing the risk of developing severe reproductive sequelae. Therefore, the present review aims to summarize the evidence on the interplay between C. trachomatis and the host defence factors within the cervicovaginal environment. The sophisticated strategies employed by this clinically significant pathogen to counteract these mechanisms are also discussed. In the literature, the main defence factors include the microbiota dominated by Lactobacillus crispatus and several molecules like lactoferrin, able to protect the cervicovaginal microenvironment against C. trachomatis through several mechanisms (e.g., EB coaggregation and competitive exclusion, as well as anti-inflammatory activity). However, the major player in clearing chlamydial infections remains the interferon-gamma (IFN-γ) produced by natural killer and T cells, via the depletion of critical nutrients for C. trachomatis such as tryptophan, or via the ubiquitylation and destruction of chlamydial inclusions. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) is often diagnosed at advanced stages, with metastasis driven by spheroid dissemination within the peritoneal cavity. We previously demonstrated that autophagy supports spheroid cell survival and suggest that it contributes to chemoresistance. Unc-51-like autophagy activating kinase 1 (ULK1), a key regulator of autophagy, has emerged as a promising therapeutic target. Here, we evaluated the effects of ULK1 inhibition via MRT68921, alone and in combination with afatinib—a tyrosine kinase inhibitor (TKI) known to induce pro-survival autophagy—in EOC. Methods: High-grade serous (HGSOC) and ovarian clear cell carcinoma (OCCC) cell lines were cultured under adherent and spheroid conditions. Immunoblotting confirmed on-target effects and modulation of autophagy. Autophagic flux was assessed using mCherry-eGFP-LC3 reporter assays. We assessed 96 dose combinations of MRT68921 and afatinib using drug combination matrices, with synergy evaluated via Synergy Finder. Promising combinations were evaluated across multiple EOC spheroid models and patient ascites-derived organoids. Results: MRT68921 inhibited ULK1 activity and reduced autophagic flux in a context-dependent manner while afatinib alone induced autophagy. Their combination produced synergistic effects at select concentrations, impairing spheroid reattachment and viability. However, MRT68921 alone significantly reduced viability across multiple EOC models, including patient ascites-derived organoids. Conclusions: This study is the first to evaluate the combined effects of MRT68921 and afatinib in epithelial ovarian cancer. Our findings demonstrate that ULK1 inhibition via MRT68921 consistently reduces cell viability across multiple ovarian cancer models, supporting ULK1 as a promising therapeutic target. In contrast, combination with afatinib produced limited and context-dependent effects, indicating that further investigation is needed to identify optimal combination strategies for ULK1-targeted therapies. Full article

Ovarian cancer is one of the deadliest gynecological malignancies, where most patients become clinically symptomatic at advanced stages of disease due to the lack of effective diagnostic screening. Despite recent advances in surgical resection and chemotherapy, recurrent ovarian cancer remains largely refractory to treatment, resulting in poor prognosis. The ovarian cancer tumor microenvironment (TME) is highly abnormal and presents a significant barrier to successful therapy. A combination of abnormal vasculature, desmoplastic extracellular matrix, and aberrantly activated hypoxic and immune-suppressive pathways culminates in promoting tumor growth, dissemination, chemoresistance, and immunosuppression. Whilst immune checkpoint inhibitors have shown success in other cancers, their application in ovarian cancer, particularly at advanced stages, remains limited. In this review, we discussed the application of tumor extracellular matrix normalizing therapies in preclinical models of advanced ovarian cancer, and their synergistic benefit to chemotherapy and immunotherapy. Collectively, these insights underscore TME normalization as a promising therapeutic strategy with the potential to improve ovarian cancer management. Full article

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases. Full article

The intensification of aquaculture practices has been accompanied by an increased incidence of bacterial diseases, leading to a greater reliance on antibiotics for disease control. Consequently, the widespread and often indiscriminate use of these compounds has contributed to the emergence and dissemination of antibiotic-resistant bacteria within aquaculture systems, posing a serious threat to animal health, environmental sustainability, and public health. In this regard, research efforts have focused on developing alternative strategies to reduce antibiotic use. Natural compounds have gained particular attention due to their well-documented antimicrobial and antibiofilm activities. In this context, the combined application of antibiotics and natural compounds has emerged as a promising approach to enhance antimicrobial efficacy while potentially mitigating the development of resistance. This review synthesizes the current knowledge on antibiotic resistance in aquaculture, highlights the role of biofilm formation as a key resistance mechanism, and critically examines the potential of antibiotic–natural compound combinations against major aquaculture pathogens, with particular emphasis on bacterial growth inhibition, biofilm disruption, and virulence attenuation. Collectively, the evidence discussed underscores the potential of synergistic strategies as a sustainable tool for improving disease management in aquaculture while supporting efforts to limit antibiotic resistance. Full article

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Porphyromonas gingivalis (Pg), a keystone pathogen of chronic periodontitis, releases outer membrane vesicles (OMVs) that act as nanoscale vehicles to disseminate virulence factors within periodontal tissues and systemically beyond the oral cavity. Although Pg-OMVs are increasingly recognized as critical mediators of host–pathogen interactions, their effects on the differentiation and function of monocyte–macrophage/osteoclast lineage cells remain unclear. Here, we examined the impact of Pg-OMVs on the differentiation of RAW264.7 monocyte/macrophage-like cells into osteoclasts (OC) and/or macrophages (MΦ) in the presence of receptor activator of nuclear factor-κB ligand (RANKL). OMVs were isolated from Pg W83 and applied to RANKL-primed RAW264.7 cells using three distinct stimulation schedules: (1) simultaneous treatment with Pg-OMVs and RANKL at Day 0; (2) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 1; and (3) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 3. In all schedules, cells were cultured for 7 days from the initial RANKL exposure. Remarkably, simultaneous exposure to Pg-OMVs and RANKL (Schedule 1) markedly suppressed osteoclastogenesis (OC-genesis) while promoting M1 macrophage polarization. In contrast, delayed Pg-OMV stimulation of RANKL-primed cells (Schedules 2 and 3) significantly enhanced OC-genesis while reducing M1 polarization. These schedule-dependent effects were consistent with altered expression of osteoclastogenic markers, including dc-stamp, oc-stamp, nfatc1, and acp5. Importantly, a monoclonal antibody against OC-STAMP counteracted the Pg-OMV-induced upregulation of OC-genesis in Schedules 2 and 3. Furthermore, levels of Pg-OMV phagocytosis were inversely correlated with osteoclast formation. Finally, co-stimulation with RANKL and Pg-OMVs (Schedule 1) enhanced macrophage migratory capacity, whereas delayed stimulation with Pg-OMVs (Schedules 2 and 3) did not. Collectively, these findings indicate that Pg-OMVs exert stage-specific effects on the OC/MΦ lineage: stimulation at early stages of RANKL priming suppresses OC-genesis and promotes M1 polarization, whereas stimulation at later stages enhances OC-genesis without inducing M1 differentiation. Thus, Pg-OMVs may critically influence the fate of the OC/MΦ unit in periodontal lesions, contributing to disease progression and tissue destruction. Full article

With the advancement of digital technology, serious games have become an essential tool for disseminating and educating individuals about cultural heritage. However, systematic empirical research remains limited with respect to how visual elements influence users’ cognitive and emotional engagement through interactive behaviors. Using the “Macau Historic Centre Science Popularization System” as a case study, this mixed-methods study investigates the mechanisms by which visual elements affect user experience and learning outcomes in digital interactive environments. Eye-tracking data, behavioral logs, questionnaires, and semi-structured interviews from 30 participants were collected to examine the impact of visual elements on cognitive resource allocation and emotional engagement. The results indicate that the game intervention significantly enhanced participants’ retention and comprehension of cultural knowledge. Eye-tracking data showed that props, text boxes, historic buildings, and the architectural light and shadow shows (as incentive feedback elements) had the highest total fixation duration (TFD) and fixation count (FC). Active-interaction visual elements showed a stronger association with emotional arousal and were more likely to elicit high-arousal experiences than passive-interaction elements. The FC of architectural light and shadow shows a positive correlation with positive emotions, immersion, and a sense of accomplishment. Interview findings revealed users’ subjective experiences regarding visual design and narrative immersion. This study proposes an integrated analytical framework linking “visual elements–interaction behaviors–cognition–emotion.” By combining eye-tracking and information dynamics analysis, it enables multidimensional measurement of users’ cognitive processes and emotional responses, providing empirical evidence to inform visual design, interaction mechanisms, and incentive strategies in serious games for cultural heritage. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

The emergence and dissemination of antimicrobial resistance (AMR) are driven by complex, interconnected mechanisms involving microbial communities, environmental factors, and human activities, with climate change playing a pivotal and accelerating role. Rising temperatures, altered precipitation patterns, and other environmental disruptions caused by climate change create favorable conditions for bacterial growth and enhance the horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs). Thermal stress and environmental pressures induce genetic mutations that promote resistance, while ecosystem disturbances facilitate the stabilization and spread of resistant pathogens. Moreover, climate change exacerbates public and animal health risks by expanding the range of infectious disease vectors and driving population displacement due to extreme weather events, further amplifying the transmission and evolution of resistant microbes. Livestock agriculture represents a critical nexus where excessive antibiotic use, environmental stressors, and climate-related challenges converge, fueling AMR escalation with profound public health and economic consequences. Environmental reservoirs, including soil and water sources, accumulate ARGs from agricultural runoff, wastewater, and pollution, enabling resistance spread. This review aims to demonstrate how the Mediterranean’s strategic position makes it an ideal living laboratory for the development of integrated “One Health” frameworks that address the mechanistic links between climate change and AMR. By highlighting these interconnections, the review underscores the need for a unified approach that incorporates sustainable agricultural practices, climate mitigation and adaptation within healthcare systems, and enhanced surveillance of zoonotic and resistant pathogens—ultimately offering a roadmap for tackling this multifaceted global health crisis. Full article

Antimicrobial resistance (AMR) is escalating worldwide, posing a serious threat to global public health by driving infections that are no longer treatable with conventional antibiotics. CRISPR–Cas technology offers a programmable and highly specific therapeutic alternative by directly targeting the genetic determinants responsible for resistance. Various CRISPR systems can restore antibiotic susceptibility and induce selective bactericidal effects by eliminating resistance genes, disrupting biofilm formation, and inhibiting virulence pathways. Moreover, CRISPR can suppress horizontal gene transfer (HGT) by removing mobile genetic elements such as plasmids, thereby limiting the ecological spread of AMR across humans, animals, and the environment. Advances in delivery platforms—including conjugative plasmids, phagemids, and nanoparticle-based carriers—are expanding the translational potential of CRISPR-based antimicrobial strategies. Concurrent progress in Cas protein engineering, spatiotemporal activity regulation, and AI-driven optimization is expected to overcome current technical barriers. Collectively, these developments position CRISPR-based antimicrobials as next-generation precision therapeutics capable of treating refractory bacterial infections while simultaneously suppressing the dissemination of antibiotic resistance. Full article

Background/Objectives: Neonatal Intensive Care Units (NICUs) constitute a highly complex clinical environment characterized by patient fragility and frequent ethically sensitive decisions. To date, systematic studies investigating how Italian NICUs address these challenges and what forms of ethics support are effectively available are lacking. The aim of this study is therefore to assess how ethical issues are managed in Italian NICUs, with particular attention to the availability, use, and perceived usefulness of clinical ethics support in everyday practice. Methods: A 25-item questionnaire was developed by adapting an existing tool for investigating clinical ethics activities to the neonatal context. Following expert review by the GIBCE (Gruppo Interdisciplinare di Bioetica Clinica e Consulenza Etica in ambito sanitario), the final instrument covered four areas (general data, experience with ethical dilemmas, tools and procedures, opinions and training needs). A manual web search identified all Italian NICUs and their clinical directors, who were asked to disseminate the survey among staff. Participation was voluntary and anonymous. Data collection was conducted via Google Forms and analyzed through qualitative thematic analysis. Results: A total of 217 questionnaires were collected. The most frequent ethical dilemmas concern quality of life with anticipated multiple or severe disabilities (72.4%) and decisions to withdraw or withhold life-sustaining treatments (64.5%). Major challenges include fear of medico-legal repercussions (57.6%) and communication divergences between physicians and nurses (49.8%). More than half of respondents (52.1%) reported no formal training in clinical ethics, and 68.7% had never developed a Shared Care Plan (Shared Document for healthcare ethics planning) as defined by the Italian Law 219/2017. Conclusions: Findings highlight marked fragmentation in ethical practices across Italian NICUs. On this basis, establishing structured and accessible CEC services could help promote consistency, reinforce shared ethical standards, and support transparent and equitable decision-making in critical neonatal care. Full article