Search Results (185)

Mesenchymal stromal cells (MSCs) are intensively investigated in oncology owing to their intrinsic tumor-homing ability and capacity to deliver therapeutic agents directly into the tumor microenvironment (TME). Recent advances in genetic engineering have enabled precise modification of MSCs, allowing controlled expression of therapeutic genes and other cargo delivery, thus improving targeting efficiency. As cellular carriers, MSCs have been engineered to transport oncolytic viruses, suicide genes in gene-directed enzyme prodrug therapy (GDEPT), multifunctional nanoparticles, and therapeutic factors such as IFN-β or TRAIL, while engineered MSC-derived extracellular vesicles (MSC-EVs) offer a promising cell-free alternative. These strategies increase intratumoral drug concentration, amplify bystander effects, and synergize with standard therapies while reducing systemic toxicity. Conversely, accumulating evidence highlights the tumor-promoting properties of MSCs: once recruited by inflammatory and hypoxic cues, they remodel the tumor microenvironment by stimulating angiogenesis, suppressing immune responses, differentiating into cancer-associated fibroblasts, and promoting epithelial-to-mesenchymal transition (EMT), ultimately enhancing invasion, metastasis, and therapy resistance. This duality has sparked both enthusiasm and concern in the oncology field. The present review outlines the paradoxical role of MSCs in oncology—ranging from their potential to promote tumor growth to their emerging utility as vehicles for targeted drug delivery. By highlighting both therapeutic opportunities and biological risks, we aim to provide a balanced perspective on how MSC-based strategies might be refined, optimized, and safely integrated into future cancer therapies. Full article

Cardiac arrest is a life-threatening emergency requiring immediate intervention, with bystander-initiated Cardiopulmonary resuscitation (CPR) being critical for survival, especially in out-of-hospital situations where medical help is often delayed. Given that over 70% of out-of-hospital cases occur in private residences, there is a growing imperative to provide widespread CPR training to the public. However, conventional instructor-led CPR training faces inherent limitations regarding spatiotemporal constraints and the lack of personalized feedback. To address these issues, this paper proposes an AI-integrated XR-based CPR training system designed as an advanced auxiliary tool for skill acquisition. The system integrates vision-based pose estimation with multimodal sensor data to assess the trainee’s posture and compression metrics in accordance with Korean regional CPR guidelines. Moreover, it utilizes a Large Language Model to evaluate verbal protocols, including requesting an emergency call that aligns with the guidelines. Experimental validation of the proof-of-concept reveals a verbal evaluation accuracy of 88% and a speech recognition accuracy of approximately 95%. Furthermore, the optimized concurrent architecture provides a real-time response latency under 0.5 s, and the automated marker-based tracking ensures precise spatial registration without manual calibration. These results confirm the technical feasibility of the system as a complementary solution for basic life support education. Full article

Background/Objectives: Cyber bystanders can choose from several different strategies during cyberbullying incidents and have a significant effect on the situation. Hence, cyber bystanders are specifically targeted by prevention programmes and research investigating variables influencing cyber bystander responses is crucial for such programmes. The aim of our study was (1) to explore contextual factors’ effect on cyberbullying incidents’ perceived severity and (2) the most frequent cyber bystander responses. We also aimed (3) to learn how the context of cyberbullying incidents affects cyber bystander responses and the joint effect of individual and contextual variables on cyber bystander responses. Methods: In total, 314 Hungarian high school students participated in our online survey (mean age = 16.15, SD = 3.28). The respondents filled in self-administered questionnaires that measured cyber bystander responses, severity of different cyberbullying incidents, empathy, moral disengagement, social desirability, and cyberbullying engagement. Results: First, our results showed that the respondents perceived public and visual cyberbullying, and when the victim was upset by it the most severe incidents. Second, in almost every condition, the two most likely cyber bystander responses were ignorance and emotional support for the victim. Third, the individual and contextual variables had a joint effect influencing cyber bystander responses except for emotional support to the victim that was only influenced by individual variables, i.e., empathy, moral disengagement, and social desirability. Conclusions: All in all, our results showed that all cyberbullying contexts were associated with cyber bystander responses and the prominent association between moral disengagement, social desirability, empathy, and prosocial cyber bystander responses. Moreover, these results could guide cyberbullying prevention to focus on cyber bystanders’ empathy training, decreasing their moral disengagement, and educating them about the effects of online contextual variables. 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

Background/Objectives: The treatment of bacterial infections is complicated by emerging antibiotic resistance. This paper identifies a novel approach with a nanoparticle that targets bacterial surface charge and is responsive to the nutrient environment (i.e., glucose) and presence of metabolically active bystander species (i.e., amylase secretion) within microbial communities. Methods: Thus, metabolically responsive composite nanoparticles (440 ± 58 nm) were fabricated via electrohydrodynamic jetting of a cationic starch polymer incorporating 5–7 nm copper nanoparticles (0.3 wt%). Starch was selected as the base polymer, as it is a common carbon source for amylase-producing bacterial communities, in particular under glucose-limited growth conditions. Results: The resulting positively charged particles effectively associated with Gram-positive Staphylococcus aureus, forming co-aggregates with bacterial cells and exhibiting antibacterial activity tenfold greater than free copper nanoparticles. In co-cultures of S. aureus and the amylase-producing bystander species, Bacillus subtilis, enzymatic degradation of the copper–starch nanoparticles increased antibacterial activity against S. aureus by 44%. Conclusions: This work highlights the potential for metabolically regulated particles as a novel paradigm for selective, narrow-spectrum antibacterial therapies that exploit ecological interactions within microbial communities. Full article

Intratumoral microbiota, once considered passive bystanders, are now recognized as active modulators of the tumor immune microenvironment (TIME)—the complex network of immune cells, stromal components, and signaling molecules within tumors—and ultimately shape immunotherapy outcomes in lung cancer. This review aims to elucidate the exact roles of intratumoral microbiota in lung cancer immuno-therapy responses and the potential mechanism, offering novel perspectives for overcoming resistance. We conducted a narrative review of the literature using a PubMed and Web of Science search of articles written in English from inception to November 2025. We summarize current evidence on the characteristics of intratumoral microbiota in lung cancer and their associations with patient outcomes following immune checkpoint inhibitor (ICI) treatment. We discuss how intratumoral microbes, their metabolites, and extracellular vesicles influence and remodel TIME, thereby either promoting or counteracting ICI efficacy. Furthermore, we explore the potential of microbial signatures as predictive biomarkers and highlight microbiota-targeted strategies—including probiotics, engineered bacteria, and rational antibiotic use—to overcome resistance and enhance clinical benefits. Collectively, available data support intratumoral microbiota as crucial modulators and promising therapeutic targets in lung cancer, and decoding their multifaceted interactions may inform precision microbiota-targeting strategies to improve patient outcomes. Full article

Bullying is increasingly understood as a group-based phenomenon in which bystanders play a critical role, yet little is known about how witnessing bullying affects bystanders’ self-esteem and academic motivation. The aim of this study was to explore adolescents’ perspectives on how witnessing bullying in school may be linked to their self-esteem and academic motivation. This qualitative study explored these experiences among 35 Swedish adolescents (22 girls and 13 boys, aged 14–16) using focus group interviews analyzed through constructivist grounded theory. The analysis generated a core category, Authenticity in witnessing bullying, reflecting how adolescents balanced empathic responses, self-image, and academic motivation when confronted with bullying. In addition, six interrelated categories emerged: (1) sympathetic wounding, (2) relationship buffering, (3) fear-driven avoidance, (4) academic shielding, (5) academic draining, and (6) normalization of bullying. Witnessing bullying affected participants’ feelings of authenticity, self-esteem, coping strategies, and academic focus. Academic motivation was shaped divergently: some students withdrew and lost motivation, while others increased focus on grades to secure transfer to a safer school environment. The theory offers a framework that is grounded in participants’ accounts that helps the understanding of how authenticity shapes the social context, emotional experience, and academic engagement. Interventions that address the emotional and motivational consequences of witnessing bullying and foster supportive school climates, empowering students to act constructively, are needed. Full article

Cardiovascular morbidity and mortality rise precipitously during the 6th–9th decades of life, identifying aging as a critical risk factor. Simultaneously, older individuals are susceptible to severe viral infection, raising the question whether shared mechanisms exist that predispose to both cardiovascular disease (CVD) and failing anti-viral immunity. The aging process causes steady decline in immune fitness (immune aging), which undermines the ability to generate protective anti-viral immune responses. Paradoxically, the aging immune system supports unopposed inflammatory pathways (inflammaging), which exacerbates tissue inflammation in CVD, specifically atherosclerosis. Here, we review the current evidence of how innate and adaptive immune aging promotes tissue-destructive inflammation in atherosclerosis while failing to fight viral infections. Further, we consider how these two disease processes mutually influence each other. We propose that mounting an effective anti-viral response induces off-target bystander activation and exhausts immune cells, ultimately exacerbating CVD. Additionally, we explore how atherosclerotic CVD impacts innate immunity through epigenetic modification of hematopoietic precursors and metabolically conditioning immune cells, leading to a dysfunctional immune system that accelerates plaque inflammation while simultaneously impairing host defense. Full article

Radiotherapy (RT) remains a cornerstone of cancer treatment, offering spatially precise cytotoxicity against malignant cells. However, emerging evidence reveals that ionizing radiation (IR) exerts biological effects beyond the targeted tumor volume, manifesting as radiation bystander effects (BEs) and other non-targeted effects (NTEs). These phenomena challenge the traditional paradigm of RT as a localized intervention, highlighting systemic and long-term consequences in non-irradiated tissues. This comprehensive review synthesizes molecular, cellular, and clinical insights about BEs, elucidating the complex intercellular signaling networks gap junctions, cytokines, extracellular vesicles, and oxidative stress that propagate damage, genomic instability, and inflammation. We explore the role of mitochondrial dysfunction, epigenetic reprogramming, immune modulation, and stem cell niche disruption in shaping BEs outcomes. Clinically, BEs contribute to neurocognitive decline, cardiovascular disease, pulmonary fibrosis, gastrointestinal toxicity, and secondary malignancies, particularly in pediatric and long-term cancer survivors. The review also evaluates countermeasures including antioxidants, COX-2 inhibitors, exosome blockers, and FLASH RT, alongside emerging strategies targeting cfCh, inflammasomes, and senescence-associated secretory phenotypes. We discuss the dual nature of BEs: their potential to both harm and heal, underscoring adaptive responses and immune priming in specific contexts. By integrating mechanistic depth with translational relevance, this work posits that radiation BEs are a modifiable axis of RT biology. Recognizing and mitigating BEs is imperative for optimizing therapeutic efficacy, minimizing collateral damage, and enhancing survivorship outcomes. This review advocates for a paradigm shift in RT planning and post-treatment care, emphasizing precision, personalization, and systemic awareness in modern oncology. Full article

Antibodies are a cornerstone of the adaptive immune response, serving as key defenders against viral infections; however, they can also act as a double-edged sword, contributing to immune-mediated pathologies. This review advances a “Yin-Yang” framework to integrate the dual activities of antibodies. The protective ‘Yin’ functions are driven by high-affinity antibodies generated through processes like somatic hypermutation and class-switch recombination. These antibodies execute viral neutralization, activate the complement system, and engage Fc receptors (FcRs) to drive antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. These mechanisms form the immunological basis of effective vaccines, which aim to elicit durable and functionally specialized antibody isotypes like IgG and mucosal IgA. Conversely, the pathogenic ‘Yang’ of the response can be detrimental. This includes antibody-dependent enhancement (ADE) of infection, notably observed with flaviviruses, and the development of autoimmunity through mechanisms like molecular mimicry and bystander activation, which can lead to conditions such as multiple sclerosis and Guillain-Barré Syndrome. The balance between protection and pathology is tipped by a confluence of factors. These include viral evasion strategies like antigenic mutation and glycan shielding, as well as host-based determinants such as genetic polymorphisms in FcRs, immune history, and the gut microbiome. Understanding these molecular determinants informs the rational design of next-generation interventions. Promising strategies, such as Fc-region glyco-engineering and the design of tolerogenic vaccines, aim to selectively promote protective functions while minimizing pathological risks, offering a clear path forward in combating viral threats. Full article

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients. Full article

Background: The global health burden of mosquito-borne viruses, including dengue, yellow fever, Zika, and chikungunya, is rising due to climate change and globalisation, which favour mosquito habitat expansion. The genetic diversity of these viruses complicates the development of virus-specific vaccines or antivirals, highlighting the need for pan-viral strategies. As the common vector for these pathogens, mosquitoes and specifically their salivary proteins represent a promising target for such interventions. Mosquito saliva, secreted into the skin during biting, has immunomodulatory effects that can enhance host susceptibility to infection, but these mechanisms are not well defined in humans. Methods: The objective of this study was to determine whether AGS-v PLUS, a vaccine targeting mosquito salivary antigens, could modulate the human skin immune response to mosquito biting and potentially promote antiviral bystander immunity. In a Phase I trial, healthy volunteers were vaccinated with AGS-v PLUS (with or without adjuvant) or placebo, and three weeks later, they were exposed to bites from Aedes albopictus and Aedes aegypti mosquitoes. Skin biopsies from bitten and unbitten sites were analysed by transcriptomic profiling. Results: In placebo recipients, mosquito biting elicited a marked adaptive immune response at 48 h, characterised by CD4⁺ Th1 and CD8⁺ T cell signatures and leukocyte recruitment. While responses to Ae. aegypti and Ae. albopictus bites were broadly similar, those to Ae. albopictus were stronger. Vaccination with AGS-v PLUS, particularly with adjuvant, enhanced Th1 and CD8⁺ T cell-associated gene expression while suppressing pathways linked to neutrophilic inflammation and epithelial stress, which together may provide enhanced antiviral capacity. Conclusions: These findings demonstrate that targeting the host response to mosquito saliva via vaccination can reprogram the skin’s immune response to mosquito bites, supporting a novel and broadly applicable pan-viral strategy to mitigate the impact of arboviral diseases. Full article

Neutrophils are the most abundant immune cells in humans and the first responders to be recruited at the site of injury. They exhibit high microbicidal activity and a combination of cytotoxic mechanisms that may lead to bystander tissue damage. However, this classical and simplistic view of the neutrophil biology has recently dramatically changed. Emerging evidence indicates an active role for neutrophils in resolution of inflammation and tissue repair. This review specifically explores the mechanisms through which neutrophils perform their anti-inflammatory and tissue-repairing roles, which are also modulated by circadian rhythms—an aspect that influences immune activity and may have implications for treatment timing. A particular focus is placed on the role of platelet-derived products in modulating local neutrophil immune responses. The remarkable phenotypic plasticity of neutrophils and their crucial role in resolving inflammation and restoring homeostasis underscore their promise as a therapeutic approach. However, their activity must be finely regulated to prevent potential tissue damage. Full article

The adhesion G protein-coupled receptor ADGRE5/CD97 is upregulated in many cancers, representing a potential drug target in oncology/immuno-oncology. Yet, ADGRE5′s activation and signaling mechanisms remain poorly understood. Here, we used enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors and three strategies to characterize human (h) ADGRE5 signaling. First, a synthetic tobacco etch virus (TEV) protease-cleavable receptor chimera enabling controlled tethered agonist (TA) exposure at the GPCR proteolysis site (GPS) revealed signaling through Gα12 and Gα13, along with the recruitment of β-Arrestins 1/2 (β-Arrs). Second, we investigated WT hADGRE5 signaling elicited by Gingipain K (Kgp), an endopeptidase that cleaves hADGRE5 upstream of the GAIN domain. Kgp mirrored TEV-induced signaling but also promoted Gαz and Gα11 activity. The abolition of hADGRE5′s GPS did not block Kgp-induced receptor activation, revealing a GPS cleavage-independent mechanism of action. Finally, we developed an assay to study hADGRE5 mechanical stimulation (MS) using β-Arr2 as a readout. MS promoted β-Arr2 recruitment in hADGRE5-expressing cells, and this response was lost upon abolition of the GPS. A neutralizing antibody to the hADGRE5 ligand CD55 significantly dampened MS-induced β-Arr2 engagement. Overall, this study advances our understanding of hADGRE5′s signaling and highlights the receptor’s plasticity in activating pathways via both GPS cleavage-dependent and -independent mechanisms. Full article

This study examined how undergraduate bystanders respond to cyber-ostracism events and the moderating role of rejection sensitivity in shaping helping behaviors using two experiments. In Experiment 1 (N = 276), we first measured participants’ rejection sensitivity, then manipulated cyber-ostracism using a social media interaction scenario, and finally, measured helping behavior towards the (non-)ostracism target using a questionnaire. Experiment 2 (N = 258) sought to replicate and extend the findings of Experiment 1 using a methodologically refined design, in which we employed a modified Cyberball paradigm to manipulate cyber-ostracism and measured bystanders’ helping behavior through their resource allocation decisions (i.e., token sharing). The results revealed that witnessing cyber-ostracism significantly promoted bystanders’ helping behavior. This facilitative effect was more pronounced among bystanders with high rejection sensitivity. These findings shed light on the psychological mechanisms underlying bystanders’ helping responses in the context of cyber-ostracism and provide a new perspective for understanding interpersonal interactions in digital environments. Full article