Search Results (324)

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2⁺OCT4⁺TERT^high subpopulations from AsPC-1 and BxPC-3 cells. We combined Fluorescence-Activated Cell Sorting with functional assays, RNA-seq, and network analysis. Clinically, tumors co-expressing high SOX2/OCT4/TERT levels were associated with reduced overall survival, whereas single-gene elevations were not prognostic. We identified a minority SOX2⁺OCT4⁺TERT^high fraction (~9%) enriched for pluripotency transcripts (SOX2, OCT4, NANOG, and ALDH1A1), which exhibited the highest proliferative, migratory, and invasive capacities. Transcriptomic profiling of SOX2⁺OCT4⁺TERT^high cells showed enrichment of KRAS, telomere maintenance, epithelial–mesenchymal transition, and developmental pathways (WNT and Hedgehog). Connectivity profiling highlighted actionable vulnerabilities, including NF-κB, WNT, and telomerase inhibition pathways. Together, these data define an aggressive telomerase-engaged, pluripotency-driven CSC-like state in PDAC and suggest testable therapeutic strategies that target TERT^high dependencies. Full article

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G₁ arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial–mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling. Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-α and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions. Full article

The Space–Air–Ground Integrated Network (SAGIN), a core architecture for 6G, faces formidable routing challenges stemming from its high-dynamic topological evolution and strong heterogeneous resource characteristics. Traditional protocols like OSPF suffer from excessive convergence latency due to frequent topology updates, while existing intelligent methods such as DQN remain confined to a passive reactive decision-making paradigm, failing to leverage spatiotemporal predictability of network dynamics. To address these gaps, this study proposes an adaptive routing algorithm (GCN-T-PPO) integrating a GCN-Transformer hybrid encoder, Particle Swarm Optimization (PSO), and Proximal Policy Optimization (PPO) with spatiotemporal attention. Specifically, the GCN-Transformer encoder captures spatial topological dependencies and long-term temporal traffic evolution, with PSO optimizing hyperparameters to enhance prediction accuracy. The PPO agent makes proactive routing decisions based on predicted network states (next K time steps) to adapt to both topological and traffic dynamics. Extensive simulations on real dataset-parameterized environments (CelesTrak TLE data, CAIDA 100G traffic statistics, CRAWDAD UAV mobility models) demonstrate that under 80% high load and bursty Pareto traffic, GCN-T-PPO reduces end-to-end latency by 42.4% and packet loss rate by 75.6%, while improving QoS satisfaction rate by 36.9% compared to DQN. It also outperforms SOTA baselines including OSPF, DDPG, D2-RMRL, and Graph-Mamba. Ablation studies validate the statistical significance (p < 0.05) of key components, confirming the synergistic gains from spatiotemporal joint modeling and proactive decision-making. This work advances SAGIN routing from passive response to active prediction, significantly enhancing network stability, resource utilization efficiency, and QoS guarantees, providing an innovative solution for 6G global seamless coverage and intelligent connectivity. Full article

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

Ultra-dense heterogeneous cellular networks in 6G and beyond face an escalating vulnerability to cell outages stemming from complex issues like parameter misconfigurations, hidden conflicts among Autonomous Network Functions (ANFs), multivendor incompatibility, and software/hardware failures. While ANF-based automated fault detection is a core capability for next-generation networks, existing solutions are predominantly reactive, identifying faults only after reliability is compromised. To overcome this critical limitation and maintain high service quality, a proactive fault prediction capability is essential. We introduce a novel Discrete-Time Markov Chain (DTMC)-based stochastic framework designed to model network reliability dynamics. This framework forecasts the transition of a cell from normal operation to suboptimal or degraded states, offering a crucial shift from reactive to proactive fault management. Our model rigorously quantifies the effects of fault arrivals, estimates the fraction of time the network remains degraded, and, uniquely, identifies sensitive parameters whose misconfigurations pose the most significant threat to performance. Numerical evaluations demonstrate the model’s high applicability in accurately predicting both the timing and probable causes of faults. By enabling true anticipation and mitigation, this framework is a key enabler for significantly reducing the cell outage time and enhancing the reliability and resilience of next-generation wireless networks. Full article

Introduction: Paternal filicide is a rare and complex form of intrafamilial homicide, frequently associated with underlying psychopathology, interpersonal conflict, and psychosocial stressors. While maternal filicide has been more extensively studied, cases involving fathers—especially those employing multiple homicidal methods—remain significantly underrepresented in the forensic literature. This paper presents an unusual case of paternal filicide involving combined lethal methods, contextualized through a narrative review of comparable cases. Methods: A comprehensive forensic-pathological and psychiatric investigation was conducted following the homicide of an 8-year-old boy, killed by his father through a combination of asphyxiation and stabbing. A narrative literature review was performed using PubMed, Scopus, and Google Scholar, focusing on case reports and case series concerning paternal filicide. Particular attention was paid to homicidal methods, motivational dynamics, psychiatric comorbidities, and post-crime behavior. Results: The child’s body was found concealed in a building, in a bed storage drawer, with packing tape tightly wrapped around the mouth and nose and a kitchen knife embedded in the neck. No defensive wounds were observed, suggesting a sudden and unopposed assault, likely facilitated by the victim’s trust in the perpetrator. Autopsy findings revealed signs of asphyxiation and three stab wounds to the chin, neck, and thorax, involving vital structures such as the thyroid cartilage and heart. The father was found in a state of acute alcohol intoxication and subsequently convicted of intentional homicide. The motive appeared to be revenge-related, stemming from a highly conflictual marital separation. The literature review confirmed the predominance of retaliatory motives, frequent substance use, and post-crime suicidal behavior. However, the use of combined homicidal methods and the concealment of the body were found to be exceedingly rare. Conclusions: This case, combined with the literature review, highlights the need for deeper scientific exploration of paternal filicide. Comprehensive forensic and psychiatric assessments are essential to identify recurring situational patterns, motivational profiles, sociocultural contexts, and psychiatric vulnerabilities. These findings are critical not only for post-crime evaluations but also for the development of interdisciplinary prevention strategies targeting early warning signs and high-risk family dynamics. Full article

Cancer cell plasticity drives metastasis and therapy resistance through dynamic transitions between epithelial, mesenchymal, and neural crest stem-like (NCSC) states; however, a unifying mechanism that stabilizes these transitions remains undefined. To address this gap, we introduce a N-cadherin (CDH2)-centered redox–adhesion–exosome (RAX) hub that links oxidative signaling, adhesion dynamics, and exosome-mediated immune communication into a closed-loop framework. Within this network, reactive oxygen species (ROS) pulses license epithelial–mesenchymal transition (EMT), AXL–FAK/Src signaling consolidates mesenchymal adhesion, and selective exosomal cargoes—including miR-21, miR-200, miR-210, and PD-L1—propagate plasticity and immune evasion. Lipid peroxidation acts as a central checkpoint connecting ROS metabolism to PUFA membrane remodeling and ferroptosis vulnerability, buffered by NRF2–GPX4 and FSP1/DHODH axes, thereby converting transient oxidative pulses into persistent malignant states. Mechanistically, the RAX hub synthesizes findings from EMT/CSC biology, ferroptosis defenses, and exosome research into a self-reinforcing system that sustains tumor heterogeneity and stress resilience. Evidence from single-cell and spatial transcriptomics, intravital ROS imaging, and exosome cargo-selector studies supports the feasibility of this model. We further outline validation strategies employing HyPer–EMT–CDH2 tri-reporters, CRISPR perturbation of YBX1/ALIX cargo selectors, and spatial multi-omics in EMT-high tumors. Clinically, tumors enriched in EMT/NCSC programs—such as melanoma, neuroblastoma, small-cell lung cancer, pancreatic ductal adenocarcinoma, and triple-negative breast cancer (TNBC)—represent RAX-dependent contexts. These insights highlight biomarker-guided opportunities to target adhesion switches, ferroptosis defenses, and exosome biogenesis through lipid peroxidation-centered strategies using liquid-biopsy panels (exosomal CDH2, miR-200, miR-210) combined with organoid and xenograft models. By linking lipid peroxidation to ferroptosis defense and oxidative stress adaptation, the RAX hub aligns with the thematic focus of lipid metabolism and redox control in cancer progression. Collectively, the RAX framework may provide a conceptual basis for precision oncology by reframing metastasis and therapy resistance as emergent network properties. Full article

Biomimicry is an engineering field where inspiration from nature is leveraged to engineer sustainable solutions. Biomimicry is not a subject typically taught in undergraduate curriculum. This study explores the effects of intercultural context on the learning of biomimicry. Visiting students from the United States of America and home students from Singapore gathered for a one-day workshop on biomimicry in Singapore. The workshop consisted of a lecture with in-class activities and laboratory experiments in groups, followed by students’ presentations. The students’ responses to pre- and post-workshop surveys are analyzed, along with their answers from the in-class activities and their presentations. The results show that the international context of the biomimicry workshop made an overall positive contribution to the motivation, appreciation, and enjoyment of all students. Some differences were observed between the visiting and home students, which likely stemmed from the visiting students being better prepared for the event. However, despite high levels of enjoyment and communication, the learning outcomes lacked technical depth and sustainability focus. This suggests the need for a consistent and higher level of preparation and guidance for all participating students on these topics. This study serves as a preliminary example of a workshop that explores the global theme of biomimicry in an international and intercultural setting. Similar workshops could be conducted with larger and more diverse student populations for more robust results. This work could inspire other educators in engineering to explore ways to prepare students for more holistic education. Full article

This paper presents the electrical characterization of the on-resistance (R_ON) of on-wafer 100 V p-GaN power High-Electron-Mobility Transistors (HEMTs). This study assesses device degradation in the context of a monolithically integrated half-bridge circuit, considering both Low-Side (LS) and High-Side (HS) configurations. Since on-wafer samples have been characterized, a custom experimental setup was developed to emulate stress conditions experienced by the devices in the half-bridge circuit. A periodic signal (T = 10 µs, T_ON = 2 µs) switching from the OFF to the ON state was applied for a cumulative duration of 1000 s. Different OFF-state stress conditions were applied by varying the gate-source OFF voltage (V_GS,OFF) between 0 V and −10 V. The on-resistance exhibited a positive drift over time for devices in either the LS or the HS configuration, with the latter showing a more pronounced degradation. Measurements at higher temperatures (up to 90 °C) were carried out to characterize the dynamics of the physical mechanism behind the degradation effects. We identified hole emission from C-related acceptor traps in the buffer as the main mechanism for the observed degradation, which is present in both the HS and the LS configurations. The additional degradation observed in the HS case was attributed to the back-gating effect, stemming from the non-null body-to-source voltage. Furthermore, we found that a more negative V_GS,OFF further increases R_ON degradation, likely related to the higher electric field near the gate contact, which enhances hole emission from C-related acceptor traps. Full article

Ovarian cancer is the sixth leading cause of cancer-related deaths among women in the United States. This complex disease arises from tissues such as the ovarian surface epithelium, fallopian tube epithelium, endometrium, or ectopic Müllerian components and is characterized by diverse histological and molecular traits. Standard treatments like surgery, chemotherapy, and radiation have limited effectiveness and high toxicity. Targeted therapies, including poly (ADP-ribose) polymerase PARP inhibitors, anti-angiogenics, and immune checkpoint inhibitors (ICIs), face obstacles such as adaptive resistance and microenvironmental barriers that affect drug delivery and immune responses. Factors in the tumor microenvironment, such as dense stroma, hypoxia, immune suppression, cancer stem cells (CSCs), and angiogenesis, can reduce drug efficacy, worsen prognosis, and increase the risk of recurrence. Research highlights impaired immune function in ovarian cancer patients as a contributor to recurrence, emphasizing the importance of immunotherapies to target tumors and restore immune function. Preclinical studies and early clinical trials found that natural killer (NK) cell-based therapies have great potential to tackle ovarian tumors. This review explores the challenges and opportunities in treating ovarian cancer, focusing on how NK cells could help overcome these obstacles. Recent findings reveal that engineered NK cells, unlike their primary NK cells, can destroy both stem-like and differentiated ovarian tumors, pointing to their ability to target diverse tumor types. Animal studies on NK cell therapies for solid cancers have shown smaller tumor sizes, tumor differentiation in vivo, recruitment of NK and T cells in the tumor environment and peripheral tissues, restored immune function, and fewer tumor-related systemic effects—suggesting a lower chance of recurrence. NK cells clinical trials in ovarian cancer patients have also shown encouraging results, and future directions include combining NK cell therapies with standard treatments to potentially boost effectiveness. Full article

Background: The epithelial-to-mesenchymal transition (EMT) process is necessary for metastasis as it enables tumor cells’ migration and invasion. In the remote organ, tumor cells can develop into metastatic lesions or arrest their proliferation and become dormant, thus suspending metastatic development. EMMPRIN is a membrane glycoprotein, implicated in cell–cell interactions, proliferation, angiogenesis, and EMT. We asked whether neutralizing EMMPRIN with the new anti-EMMPRIN monoclonal antibody hMR18-mAb can inhibit EMT. Methods: We co-cultured tumor cell lines (breast carcinoma MCF-7, MDA-MB-231, or oral squamous cell carcinoma SCC-40) together with U937 monocytic-like cells, with or without hMR18-mAb or its negative control rabbit IgG. Results: We demonstrate that depending on the initial state of the cells along the epithelial–mesenchymal axis (E/M axis), co-culture enhanced the EMT process, whereas hMR18-mAb reversed this effect. The co-culture increased EMT-inducer cytokines in all cell lines (by 2.5-fold), while hMR18-mAb reduced them (by ~55–70% in the breast cancer cells and by 81% in the SCC-40 cells). The co-culture reduced E-cadherin (by 2-fold in MCF-7 and SCC-40 cells) and increased vimentin expression (by 2–3-fold in MDA-MB-231 and SCC-40), while hMR18-mAb reverted this effect. Co-culture enhanced proliferation, migration, and angiogenic potential of the tumor cells, while hMR18-mAb reduced these by ~20%, 30–44% and ~60–80%, respectively. Co-culture reduced the standard markers of dormancy (NR2F1, p21, p27) and stemness (SOX2, Nanog) (by 30–60% in MCF-7 and SCC-40), while hMR18-mAb elevated gene expression of these markers (by 1.5–3.5-fold) in all cell lines, pushing the cells towards dormancy. Conclusions: We conclude that EMMPRIN is a gatekeeper that prevents cells from entering dormancy, and that hMR18-mAb disrupts this effect. As it is the first antibody shown to induce dormancy in tumor cells and stop the development of metastases, this could become a new therapeutic strategy to prevent and treat metastasis. Full article