Search Results (76)

HER2-positive breast cancer accounts for 15–20% of all breast cancers. The introduction of anti-HER2 therapies has markedly improved the clinical outcomes; however, overcoming drug resistance in metastatic disease remains a major challenge. This review summarizes the multilayered mechanisms of resistance to trastuzumab and pertuzumab and outlines the rationale for sequential treatment strategies based on the emerging evidence. Resistance arises through diverse and often coexisting mechanisms, including structural alterations in the HER2 receptor (e.g., p95HER2 and HER2 mutations), constitutive activation of the PI3K–AKT–mTOR pathway, and engagement of bypass signaling through receptors such as HER3 and IGF-1R, as well as immune evasion and metabolic reprogramming. Given this complexity, the strategic sequencing of agents with distinct mechanisms of action is critical beyond first-line therapy. Trastuzumab deruxtecan demonstrates substantial antitumor activity through potent cytotoxic effects and a bystander effect, supporting its efficacy in tumors with intratumoral heterogeneity or downstream pathway activation. In contrast, tucatinib-based regimens represent an important option for patients with brain metastases and tumors expressing p95HER2. The ongoing development of novel antibody–drug conjugates and bispecific antibodies is expected to further advance personalized sequential therapy targeting composite resistance mechanisms. 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

Based on the theoretical framework of psychological barriers among third-party bystanders in school bullying contexts, grounded in Protection Motivation Theory and Ecological Systems Theory, this study developed and validated the “Adolescent Bystander Intervention Barrier Perception Scale” (ABIBPS). The initial item pool was developed through literature review and semi-structured interviews, followed by item analysis, exploratory and confirmatory factor analyses across three samples (middle school students, N = 388; middle school students, N = 474; upper elementary school students, N = 547). Results revealed a robust two-factor structure comprising “Personal Risk and Fear Perception” and “Intervention Efficacy and Outcome Uncertainty.” The scale demonstrated measurement invariance across different age groups, good internal consistency reliability, structural validity, and criterion-related validity. Correlation analyses indicated that adolescent bystander intervention barrier perceptions were significantly negatively associated with prosocial behavior, positive youth development, intentional self-regulation, and self-esteem. This study provides a valid measurement tool for understanding the psychological barrier mechanisms of bystander behavior in school bullying, offering significant theoretical and practical implications for promoting active intervention behaviors among adolescents. Full article

This study investigated the impact of sexual and bystander harassment experiences on work attitudes, stress, withdrawal, and psychological well-being of part-time employees. Participants included 314 female employees who worked part-time in their organizations. All participants completed a computer-administered workplace experience survey assessing various aspects of their work environment, including personal and bystander harassment experiences, work-related attitudes (supervisor satisfaction, coworker satisfaction, and general job stress), work behaviors (work and job withdrawal), and psychological well-being. Experiences of sexual harassment and bystander harassment were predicted to be negatively related to satisfaction and psychological health and positively related to stress and withdrawal. Both forms of harassment were expected to contribute additively to the prediction of work outcomes and psychological health. Moderator models were examined to explore the potential interactions between sexual and bystander harassment. Results indicated that both forms of harassment were related to work attitudes, stress, and withdrawal. Sexual harassment was the strongest predictor of work outcomes. Discriminant Function Analysis provided additional support for group-based distinctions. The results are discussed in terms of interpersonal and organizational implications, limitations, and future research directions. Full article

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive dilation and weakening of the abdominal aortic wall. Despite advances in surgical repair, rupture remains associated with mortality rates exceeding 65%, and no effective pharmacological therapy exists to prevent disease progression. Increasing evidence highlights chronic inflammation, extracellular matrix degradation, and immune dysregulation as central drivers of AAA pathogenesis. Among these mechanisms, the thrombospondin-1 (TSP1)–CD47 signaling axis has emerged as a critical upstream regulator of vascular inflammation. By engaging CD47, TSP1 promotes macrophage activation, impairs efferocytosis, and sustains a self-perpetuating inflammatory loop that accelerates tissue destruction. This positions the TSP1–CD47 pathway as more than a bystander in aneurysm biology, linking immune activation with structural failure of the aortic wall. The therapeutic relevance of this axis is underscored by the development of CD47-targeted agents in oncology, which restore phagocytosis and immune balance. Repurposing such strategies for vascular medicine, in combination with advanced drug delivery systems, offers a promising avenue for disease-modifying therapy in AAA. Notably, two targeted drug delivery approaches have been described: both employ bispecific targeting of CD47 in combination with a macrophage-specific marker, using immunotoxins encapsulated in liposomal carriers to enhance selectivity and therapeutic efficacy. By shifting focus from structural repair to immune modulation, targeting the TSP1–CD47 axis with these strategies has the potential to redefine the clinical management of this condition. 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

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