Search Results (69)

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

Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian cancer, renal cell carcinoma, as well as, less frequently, cholangiocarcinoma, uterine serous carcinoma, glioma, lung, pancreatic and thyroid cancers. The characteristic of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited antibody-drug conjugate (ADC) target. Methods: We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. We further characterized the pharmacological activities of CUSP06 in multiple in vitro and in vivo models. Results: CUSP06 was selectively bound to cell surface CDH6 and was efficiently internalized into CDH6-positive ovarian cancer cells, and led to the induction of DNA damage and apoptosis of CDH6-positive cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6-positive cancer cell lines and demonstrated strong bystander cell killing effect in the cell mixing experiments in vitro. CUSP06 exhibits excellent in vivo antitumor efficacy in CDH6-high or -low cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models from human ovarian, renal and uterine cancers, as well as cholangiocarcinoma. CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. Conclusions: The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers. Full article

Bone integrity is maintained through continuous remodeling, orchestrated by the coordinated actions of osteocytes, osteoblasts, and osteoclasts. Once considered passive bystanders, osteocytes are now recognized as central regulators of this process, mediating biochemical signaling and mechanotransduction. Malfunctioning osteocytes contribute to serious skeletal disorders such as osteoporosis. Mesenchymal stromal cells (MSCs), multipotent stem cells capable of differentiating into osteoblasts, have emerged as promising agents for bone regeneration, primarily through the paracrine effects of their secreted exosomes. MSC-derived exosomes are nanoscale vesicles enriched with proteins, lipids, and nucleic acids that promote intercellular communication, osteoblast proliferation and differentiation, and angiogenesis. Notably, they deliver osteoinductive microRNAs (miRNAs) that influence osteogenic markers and support bone tissue repair. In vivo investigations validate their capacity to enhance bone regeneration, increase bone volume, and improve biomechanical strength. Additionally, MSC-derived exosomes regulate the immune response, creating pro-osteogenic and pro-angiogenic factors, boosting their therapeutic efficacy. Due to their cell-free characteristics, MSC-derived exosomes offer benefits such as diminished immunogenicity and minimal risk of off-target effects. These properties position them as promising and innovative approaches for bone regeneration, integrating immunomodulatory effects with tissue-specific regenerative capabilities. Full article

Augmented Reality Smart Glasses (ARSGs) allow users to engage in picture-taking and video recording, as well as real-time storage and sharing of pictures and videos through cloud services. Unlike smartphones, newer ARSGs resemble ordinary sunglasses, allowing for unobtrusive recording. As these devices become available on an international market, it is important to understand how different cultural attitudes towards privacy and the recording and sharing of images of bystanders could impact the acceptance and adoption of ARSGs. South Korea and the United States have vastly different culturally based perceptions of photography and recording in public. S. Korea has cultural and legal restrictions in place, while the U.S.’s values of freedom of expression and individual rights are reflected in limited restrictions. Accordingly, drawing upon the Technology Acceptance Model (TAM), this paper explored the impact of privacy concerns on key constructs of the TAM for U.S. and S. Korean participants. This paper examined how Americans’ (U.S. = 402) and S. Koreans’ (S. Korea = 898) perceived usefulness, perceived ease of use, attitude toward using, and behavioral intention to use ARSGs were impacted by privacy concerns. The results of this study found that S. Korean respondents had significantly greater privacy concerns about using ARSGs than U.S. respondents. However, they also had significantly more positive attitudes and greater behavioral intentions to use ARSGs. Path analyses examining ARSGs’ acceptance revealed that privacy concerns impacted attitudes towards ARSGs, but that these had a greater impact on U.S. participants than on Koreans. The results highlight the importance of considering nuanced cultural perspectives, specifically privacy concerns, in examining the development and adoption of new technologies. Raw data and scripts for this study are available to ensure reproducibility. Full article

Nitric oxide (NO), the first gaseous molecule identified as a signaling mediator, plays a pivotal role in numerous physiological processes including cardiovascular regulation, immune response, and neurotransmission. Synthesized from L-arginine by nitric oxide synthase (NOS), NO exerts both protective and cytotoxic effects depending on its local concentration. At low levels, NO supports tumor growth by mitigating oxidative stress, while at high concentrations, it induces apoptosis through mechanisms such as p53 activation, cytochrome c release, and peroxynitrite formation. These dual properties position NO as a complex but promising agent in cancer therapy. Recent studies have highlighted the potential of NO in enhancing the efficacy of photodynamic therapy (PDT), where it synergizes with reactive oxygen species (ROS) to induce cytotoxic effects in tumor cells. Despite its promise, challenges such as rapid diffusion and limited tumor accumulation hinder NO’s therapeutic utility. This has spurred the development of NO donors and nanotechnology-based delivery systems to enable controlled, site-specific release. Moreover, NO has been shown to counteract multidrug resistance, improve tumor perfusion by dilating vasculature, and potentiate ROS-based therapies like PDT and radiotherapy. However, an emerging concern is NO’s role in promoting proliferation and migration of non-targeted “bystander” tumor cells following PDT-induced stress, primarily through iNOS upregulation. This feedback loop can contribute to tumor aggressiveness and metastasis, underscoring the need for a deeper understanding of NO’s molecular actions. While iNOS inhibitors show preclinical promise in various inflammatory and neoplastic conditions, no such agents have reached clinical approval, due to the complexity and context-dependent effects of NO. Future research should focus on refining NO delivery systems, developing selective iNOS inhibitors, and elucidating NO’s dual role in cancer biology to fully harness its therapeutic potential in PDT and beyond. Full article

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic inflammatory condition encompassing ulcerative colitis (UC) and Crohn’s disease (CD). The role of environmental factors in the pathogenesis of IBD remains elusive. Nevertheless, evidence suggests a pivotal role of viruses, specifically Epstein–Barr virus (EBV), in the progression of IBD through mechanisms such as molecular mimicry and bystander activation. Our previous findings demonstrate EBV DNA’s significant role in exacerbating colitis symptoms and elevating the levels of the pro-autoimmune cytokine interleukin-17A (IL-17A) in an IBD mouse model via toll-like receptor 9 (TLR9). Therefore, we aimed to examine the role of EBV particles in the pathogenesis of IBD, and the potential role of TLR9 inhibition in ameliorating disease outcomes. Methods: Three days post colitis induction, EBV particles were intra-rectally injected into female C57BL/6J mice, followed by the intra-peritoneal administration of TLR9 inhibitor. Thereupon, mice were monitored daily and the disease activity index (DAI), colon lengths, and damage scores, as well as the number of cells, double-positive for IL-17A+ and IFN-γ+, and triple-positive for IL-17A+, IFN-γ+, and FOXP3+, were evaluated. Results: Our findings revealed a significant role of TLR9 inhibition in mitigating colitis features in an EBV-injected IBD mouse model compared to the control group. Conclusions: These results indicate an essential role of TLR9 in initiating immune responses against recurrent EBV reactivation events, which ultimately contributes to inflammation aggravation in IBD patients. Consequently, TLR9 could serve as a potential therapeutic target to alleviate the severe symptoms of IBD in EBV-infected individuals. Full article

Background/Objectives: Bystander first aid in paediatric choking is crucial. It ought to be universally comprehensible and backed up by evidence-based guidelines. However, there still are inconsistencies in guidelines worldwide. The objective of this research was to assess the knowledge of medical students on paediatric choking rescue manoeuvres and their educational backgrounds in order to evaluate the impact of differences in educational curricula. Methods: Medical students from a total of 12 universities across Canada, Libya, and Poland were surveyed online. The questionnaire assessed the respondents’ experience, training, and knowledge in first aid regarding foreign body airway obstruction in infants and children. Results: Out of 324 responses, 290 were evaluated. Although the students studied in only 3 countries, they represented 37 countries of origin. A total of 7 new reference groups were created based on guideline identification. A comparison of 4 clinical scenario questions revealed that certain training providers communicate recommendations more effectively to medical students, as their guidelines seem to have better knowledge retention. Conclusions: There are important differences in medical student knowledge, possibly due to discrepancies in training programs and guidelines. Variability was found in body position, anti-choking suction devices, blind finger sweeps, and medical follow-ups. More research is needed to standardize training and improve worldwide choking management outcomes. Full article

Radiation therapy is a medical treatment that uses high doses of radiation to kill or damage cancer cells. It works by damaging the DNA within the cancer cells, ultimately causing cell death. Radiotherapy can be used as a primary treatment, adjuvant treatment in combination with surgery or chemotherapy or palliative treatment to relieve symptoms in advanced cancer stages. Radiation therapy is constantly improving in order to enhance the effect on cancer cells and reduce the side effects on healthy tissues. Our results clearly demonstrate that proton therapy and, even more, carbon ion therapy appear as promising alternatives to overcome the radioresistance of various tumors thanks to less dependency on oxygen and a better ability to kill cancer stem cells. Interestingly, hadrons also retain the advantages of radiosensitization approaches. These data confirm the great ability of hadrons to spare healthy tissue near the tumor via various mechanisms (reduced lymphopenia, bystander effect, etc.). Technology and machine improvements such as image-guided radiotherapy or particle therapies can improve treatment quality and efficacy (dose deposition and biological effect) in tumors while increasingly sparing healthy tissues. Radiation biology can help to understand how cancer cells resist radiation (hypoxia, DNA repair mechanisms, stem cell status, cell cycle position, etc.), how normal tissues may display sensitivity to radiation and how radiation effects can be increased with either radiosensitizers or accelerated particles. All these research topics are under investigation within the ARCHADE research community in France. By focusing on these areas, radiotherapy can become more effective, targeted and safe, enhancing the overall treatment experience and outcomes for cancer patients. Our goal is to provide biological evidence of the therapeutic advantages of hadrontherapy, according to the tumor characteristics. This article aims to give an updated view of our research in radiation biology within the frame of the French “ARCHADE association” and new perspectives on research and treatment with the C400 multi-ions accelerator prototype. Full article

Background/Objectives: Implantable loop recorders (ILRs) are widely used for the diagnosis of unexplained syncope, palpitations, and cryptogenic stroke. While ILRs demonstrate clinical utility, data on their diagnostic yield and value in real-world settings remain limited. This study evaluates ILR performance, diagnostic yield, and clinical impact across multiple indications. Methods: We retrospectively analyzed 316 patients who underwent ILR implantation between 2017 and 2023 at a single center. Indications included unexplained syncope, palpitations, and atrial fibrillation (AF) detection. Diagnostic yield, defined as the ratio of positive diagnoses to implants, and diagnostic value, defined as diagnoses leading to therapeutic changes, were assessed. Diagnostic appropriateness, reflecting diagnoses consistent with implant indications, was also investigated. Continuous variables were analyzed using an independent samples t-test or ANOVA, when appropriate; dichotomous variables were analyzed using a chi-square test. Results: The overall diagnostic yield was 30%, with most diagnoses occurring within 24 months post-implantation. Bradyarrhythmias were diagnosed earlier (mean: 290 days) than tachyarrhythmias (590 days, p = 0.04). The diagnostic value was 29%, and the appropriateness reached 70%. The diagnostic-value-to-diagnostic-yield ratio was shown to be as high as 97%, suggesting that whenever a diagnosis was made, it was of clinical impact. Patients with presyncope showed a higher diagnostic yield, particularly for tachyarrhythmias. Device re-implantation showed limited utility, as only one diagnosis (classified as bystander) was achieved in 32 re-implanted patients. After 900 days, the diagnostic yield decreased significantly, with the number needed to follow (NNF) rising from 3.85 to 18 (p < 0.001). Conclusions: ILRs are effective for arrhythmia detection, demonstrating significant diagnostic and therapeutic impact, particularly within the first two years. The recurrence of presyncope and atrial dilation was associated with higher yields, while isolated syncope posed diagnostic challenges. Prolonged monitoring beyond 900 days and device re-implantation provided diminishing returns. Full article

The primary objective of this short-term longitudinal study was to investigate how age groups affect the relationships between cyberbullying victimization, bystanding, and depression among a convenience sample of students across different educational levels; there was a total of 234 elementary school students (fourth and fifth graders), 363 middle school students (sixth to eighth graders), and 341 high school students (ninth to twelfth graders) from the United States who completed self-reported questionnaires on cyberbullying, depression, and peer attachment during 2020. Additionally, this study examined whether peer attachment acted as a moderator in these relationships. The results revealed that strong peer attachment significantly moderated the connections between cyberbullying involvement and depression, as measured six months later, with particularly pronounced effects among middle school students. In contrast, weaker peer attachment intensified the positive correlations between cyberbullying victimization, bystanding, and subsequent depression. These findings highlight the crucial role of cultivating strong peer relationships, especially during pivotal developmental phases such as middle school. Implementing programs that promote positive peer interactions and supportive networks can be effective at alleviating the psychological effects of cyberbullying. Full article

Catheter ablation for ventricular tachycardia (VT) in patients with systolic heart failure remains a critical yet challenging area of non-pharmacological therapy. Despite positive outcomes in atrial fibrillation, evidence for the efficacy of VT ablation in reducing cardiac mortality is inconclusive due to the absence of standardized ablation strategies. The primary challenges include difficulties in identifying suitable ablation targets and their deep locations within myocardial tissue. Current techniques, such as voltage mapping, provide valuable insights; however, they are limited by the presence of numerous bystander areas and the occurrence of incomplete transmural scarring. Recent advancements in functional substrate mapping have focused on identifying critical isthmuses without requiring hemodynamic stabilization during VT, thereby shifting the emphasis to the analysis of potentials during baseline rhythm. While methods like isochronal late activation mapping have improved target identification, they primarily address conduction abnormalities without adequately considering repolarization heterogeneity. This review highlights emerging technologies that utilize unipolar potentials to assess repolarization heterogeneities and identify VT isthmuses. Furthermore, novel ablation sources such as pulsed-field ablation, bipolar ablation, and ultra-low temperature cryoablation are being explored to create deeper and more durable lesions, addressing the limitations of traditional radiofrequency ablation. These advancements aim to reduce VT recurrence and improve overall treatment efficacy. Ultimately, understanding these innovative strategies is expected to optimize procedural outcomes and significantly enhance the management of patients with scar-related VT. Full article

Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME’s active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME. Full article

While numerous studies have revealed the impact of different bullying behaviors, such as victimization and perpetration, on the psychological development of adolescents, the exploration of the correlates of positive/negative bystander behaviors and their potential underlying mechanisms remains scarce in China. The present study aims to compare the relationships between mental health and positive versus negative bystander behavior and to clarify whether self-efficacy and coping styles mediate the relationships between mental health and bullying dynamics. The current study was conducted on 11,734 students from 18 secondary schools in Suzhou, China (Mean_age = 15.00, SD_age = 1.47; 53.8% boys). The information on bullying victimization, perpetration, positive/negative bystander behaviors, as well as self-efficacy, coping styles and mental health variables (including depression, anxiety, sleep disturbance, suicide risk), were collected. Negative bystander behavior was positively associated with mental health problems, while positive bystander behavior was negatively associated with these factors. Also, further analysis showed that coping styles and self-efficacy mediated the relationship between different bullying behaviors and mental health outcomes. The results highlighted the comparison of the correlates of positive and negative bystander behaviors, which were comparably crucial to those of victims and perpetrators for prevention and intervention efforts. Promoting adaptive coping styles and self-efficacy to buffer the deleterious psychological consequences of bullying behavior in adolescents was also important. Full article

With the improvement of medical devices for diagnosis and radiotherapy, concerns about the effects of low doses of ionizing radiation are also growing. There is no consensus among scientists on whether they might have beneficial effects on humans in certain cases or pose more risks, making the exposure unreasonable. While the damaging consequences of high-dose radiation have been known since the discovery of radioactivity, low-dose effects present a much bigger investigative challenge. They are highly specific and include radio-adaptive responses, bystander effects, and genomic instability. Current data regarding the consequences of exposure to low-dose radiation on the quality of male gametes and fertility potential are contradictory. The reports suggest two directions: indirect impact on male gametes—through spermatogenesis—or direct effects at low doses on already mature spermatozoa. Although mature gametes are used for observation in both models, they are fundamentally different, leading to varied results. Due to their unique physiological characteristics, in certain cases, exposure of spermatozoa to low-dose ionizing radiation could have positive effects. Despite the findings indicating no beneficial effects of low-dose exposure on male fertility, it is essential to research its impact on mature spermatozoa, as well. Full article

Background/Objectives: The primary objective of this research was to assess age differences in the associations between cyberbullying victimization and bystanding and depression among 234 elementary school students (4th and 5th graders; 51% female), 363 middle school students (6th to 8th grades; 53% female), and 341 high school students (9th to 12th grades; 51% female) as well as the moderating effect of parental mediation in these relationships. Methods: Participants completed self-report questionnaires on their cyberbullying victimization and bystanding, as well as depressive symptoms. Results: The findings revealed that high levels of instructive mediation buffered against depression associated with cyberbullying victimization and bystanding across all age groups, with the strongest effects found for middle school students. Lower levels of instructive mediation and higher levels of restrictive mediation increased the positive relationships between cyberbullying victimization and bystanding and depression. Co-viewing mediation did not moderate any of the associations. Conclusions: Parental mediation of technology use has the potential to alleviate the negative consequences associated with cyberbullying victimization and bystanding. The findings highlight the importance of tailoring prevention and intervention strategies to specific age groups and to parents. Full article