While radiotherapy excels at local tumor control, it seldom orchestrates durable systemic immunity in the context of metastatic disease. The abscopal effect, the regression of non-irradiated distant lesions following focal irradiation, remains a clinical rarity rather than a predictable or robust consequence of monotherapeutic radiotherapy. Clinical manifestations of this phenomenon predominantly emerge within the framework of combinatorial radio-immunotherapy, specifically alongside immune checkpoint blockade, rather than as a byproduct of radiotherapy in isolation. This clinical reality underscores that radiotherapy-induced immunogenic cell death (ICD), though mechanistically pivotal, is rarely self-sufficient in catalyzing systemic antitumor immunity. We contend that the variability of the abscopal response cannot be ascribed solely to the presence or magnitude of radiotherapy-induced ICD; rather, it hinges decisively on how these ICD signals are "interpreted" across heterogeneous tumor microenvironments (TMEs). We propose a "priority pathway": a functionally dominant, TME-dictated axis of ICD signaling that orchestrates immune cell polarization, infiltration dynamics, and the overall trajectory of the antitumor response. Under this paradigm, uniform ICD signals, encompassing calreticulin exposure, ATP release, HMGB1 signaling, and cGAS-STING activation, yield profoundly divergent outcomes, contingent upon stromal architecture, myeloid landscapes, vascular integrity, and metabolic constraints. We present testable predictions and delineate the dynamic, temporal shifts in post-irradiation pathway dominance, offering a mechanistic rationale for the heterogeneity and transience of the abscopal effect. We synthesize these insights into an investigational precision strategy designed to remodel the TME and augment ICD signaling in a phased manner, thereby breaching immunosuppressive barriers, potentiating T-cell-mediated systemic immunity, and enhancing the reproducibility of abscopal responses in radio-immunotherapy. These propositions are intended to catalyze future preclinical and clinical inquiry, serving as a hypothesis-generating framework rather than a set of established clinical doctrines.

Achieving precise, untethered manipulation at the millimeter scale remains a fundamental challenge in minimally invasive medicine. Magnetic milligrippers have emerged as promising untethered tools for grasping, transporting, and releasing objects in confined anatomical environments, yet most existing rigid designs rely on multi-component assemblies with dedicated hinges or joints that require complex fabrication processes. Here, we present a simple, cost-effective rigid magnetic milligripper based on a folded titanium structure with two inclined permanent magnets. Actuated by a three-axis Helmholtz-Maxwell coil system, it enables orientation and translation control, as well as reversible opening. The actuation platform is coupled to a joystick-based control interface, allowing intuitive, real-time steering and opening of the milligripper by a single operator. The design is established with an analytical magnetic dipole model and validated through both finite-element simulations and experimental characterization, which together confirm reproducible, fully elastic operation across the investigated actuation range. The strong agreement between analytical, numerical, and experimental results establishes this architecture as a mechanically robust and scalable proof-of-concept platform for magnetic micromanipulation, with direct relevance to future minimally invasive biomedical applications.

KRAS mutations represent the most common oncogenic driver in Western NSCLC and a major therapeutic challenge historically deemed "undruggable." The approval of allele-specific KRAS G12C inhibitors has transformed management, yet overall survival gains remain modest and resistance is inevitable. Rapid advances in next-generation KRAS inhibitors, rational combinations, and mutant-specific strategies (G12D, G12V) necessitate an updated synthesis of evolving evidence. To critically review the therapeutic landscape of KRAS-mutant NSCLC, covering biological underpinnings, clinical efficacy of approved and investigational inhibitors, mechanisms of resistance, combination strategies, and emerging paradigms likely to redefine future standards of care. A comprehensive narrative review of published clinical trials, translational studies, resistance-mechanism analyses, and real-world datasets focusing on KRAS-mutant NSCLC. Key sources include phase I-III trials of sotorasib, adagrasib, next-generation G12C inhibitors, mutant-specific G12D inhibitors, and ongoing combination studies integrating KRAS blockade with immunotherapy, MAPK-axis inhibitors, SHP2/SOS1 inhibitors, EGFR/MET inhibitors, and chemotherapy. Sotorasib and adagrasib achieve ORRs of 37-43% and median PFS ~ 6-7 months in previously treated KRAS G12C NSCLC, with improved tolerability over docetaxel. Next-generation inhibitors (olomorasib, divarasib, glecirasib, D-1553, IBI351) demonstrate ORRs 45-55% and, in some studies, PFS exceeding first-generation agents, while emerging KRAS G12D inhibitors show early proof-of-concept activity. Resistance arises through on-target KRAS alterations, RTK-RAS bypass signaling, MAPK/PI3K pathway reactivation, and co-mutation-driven phenotypic remodeling. Combination strategies-particularly KRAS inhibitor + PD-1 blockade, SHP2/SOS1 inhibition, EGFR/MET inhibition, or platinum doublets-are yielding higher response rates and deeper, more durable suppression in early trials. KRAS-mutant NSCLC is transitioning from historically untargetable disease to a therapeutically actionable subset. Future progress hinges on resistance-directed combinations, biomarker-guided personalization, expansion to non-G12C mutants, and evaluation in earlier disease settings.

Carbacetam is a synthetic β-carboline with clinical neuroprotective potential whose primary targets include quinone reductase 2 (QR2), neuronal L-type calcium channels (Cav1.2), DYRK1A kinase, and the GABA-A receptor. To evaluate whether this polypharmacological profile provides a mechanistic basis for its efficacy, a two-arm study using a standardised weight-drop moderate traumatic brain injury (TBI) model was conducted in 125 male Wistar rats. Subjects received intraperitoneal Carbacetam (5 mg/kg/day) for 10 days, followed by longitudinal assessments of spatial behaviour, neurohumoral dynamics (hypothalamic-pituitary-adrenal, somatotropic, and vasopressinergic axes), neurological deficits, mortality, and predictive molecular docking. Carbacetam significantly attenuated post-traumatic mortality, yielding a 30-day survival probability of 81.2% compared to 33.2% in untreated TBI controls (log-rank χ[2](1) = 15.23, p = 9.51 × 10[-5]; Cox proportional-hazards ratio = 0.23, 95% CI 0.10-0.51), corresponding to a 3.55-fold reduction in cumulative 30-day mortality incidence (66.8% vs 18.8%). Behaviourally, the treatment reduced early post-traumatic freezing by 39% and increased mobility by 57% at day 7, with subjects converging toward a non-injured behavioural phenotype by day 45. Treatment significantly accelerated the recovery of reflexive capacity by day 7 (p = 0.003). Neurohumorally, acute post-traumatic hypercortisolism was heavily suppressed (p = 0.008); growth hormone and vasopressin concentrations among surviving Carbacetam-treated animals remained comparable to non-injured reference values through day 30. In silico docking predicted that Carbacetam exhibits nanomolar-range QR2 binding affinity via extensive π-π stacking with the FAD cofactor, alongside predicted secondary structural engagements at the Cav1.2 dihydropyridine site, the canonical DYRK1A hinge-region, and the transmembrane GABA-A neurosteroid pocket. This study provides converging behavioural, neuroendocrine, and computational evidence that Carbacetam exerts neuroprotective effects in experimental TBI consistent with a concentration-dependent, multi-target ligand profile, offering a theoretical structural-to-physiological rationale, pending direct mechanistic validation, for its re-evaluation in neurotraumatology.

Accurate estimation of medial and lateral knee compartment loading is crucial for understanding joint mechanics. The traditional two-step approach, which first estimates musculotendon forces and then derives joint reaction forces and moments, is often followed by a simplified 2D load-balancing method to compute tibiofemoral contact forces in the frontal plane. This study investigated the effect of full 3D knee equilibrium on tibiofemoral contact and ligament force estimation. Gait data from 48 healthy participants were analyzed using a lower-limb musculoskeletal model. The tibiofemoral joint was modeled as a hinge with a moving axis. Joint reaction forces and moments were obtained by subtracting musculotendon forces estimated via static optimization from the intersegmental loads derived through inverse dynamics. Medial and lateral contact forces were then computed either with the 2D or the proposed 3D load-balancing method, which uses all joint reaction load components to estimate ligament and contact forces. The 3D method yielded significantly higher medial and lateral contact forces throughout stance, peaking at 2.50 BW and 1.82 BW, respectively. Ligament forces peaked at 1.05 BW for the ACL, 1.12 BW for the PCL, and 0.44 BW for the LCL, with the MCL largely unloaded. Non-negligible least-squares residuals were observed, indicating limitations in force balance. The 3D load-balancing method revealed physiologically implausible loading patterns arising from joint reaction loads, particularly elevated internal/external rotation moments, computed after independently estimating musculotendon forces in the classical two-step approach. The 2D load-balancing approach is blind to these outcomes. Future work should favor one-step approaches that simultaneously resolve musculotendon, ligament, and contact forces.

Janus kinases (JAKs) are central mediators of cytokine-driven signal transducer and activator of transcription (STAT) signaling, and dysregulation of the JAK-STAT axis is implicated in inflammatory, autoimmune, and neoplastic diseases. To identify new small-molecule inhibitors of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), we implemented an integrated virtual screening workflow combining structure-based docking and ligand-based prioritization using the InterBioScreen (IBS) compound library. A drug-likeness filter reduced 521,627 IBS molecules to 116,064 candidates, which were then docked into the ATP-binding sites of JAK1 (PDB ID: 4EI4) and JAK2 (PDB ID: 6VGL) using Glide SP; compounds were prioritized using docking score thresholds of <- 8.5 kcal/mol (JAK1) and <- 9.0 kcal/mol (JAK2), yielding 407 JAK1- and 298 JAK2-focused hits. Subsequent analysis shortlisted 42 candidates for enzymatic evaluation. In vitro kinase assays identified multiple nanomolar inhibitors, including compound 1-3 (IC50 = 0.032 μM) among the most potent for JAK1 and compound 2-8 (IC50 = 0.026 μM) for JAK2. Finally, 100 ns molecular dynamics (MD) simulations supported stable binding for representative complexes, with persistent hinge-region interactions for compound 1-3 in JAK1 (e.g., Glu957/Leu959) and compound 2-8 in JAK2 (e.g., Glu930/Leu932), consistent with a stable interaction network in the active site. Collectively, these results define validated IBS-derived hit scaffolds for further optimization and selectivity profiling toward JAK-targeted therapeutics.

The ankle joint complex is a sophisticated structure whose kinematic behaviour is frequently oversimplified in both clinical and biomechanical practice. The hinge model, with a fixed axis aligned with the line joining medial and lateral malleoli, remains prevalent despite evidence of a migrating centre of rotation (COR) and three-dimensional motion. This paper addresses common misconceptions surrounding the COR and axis of rotation (AOR) at the ankle joint, clarifying their purely kinematic nature. A conceptual framework is provided, introducing mechanical notions of COR, centrode, helical axis and axode with reference to their application in the ankle joint analysis. The clinical relevance of accurate COR localisation is discussed, spanning the topics of muscles moment arm estimation and total ankle arthroplasty (TAA). Current limitations are critically reviewed, including the absence of standardised in vivo protocols and the insufficient integration of subject-specific kinematic assessment. Emerging acquisition technologies are proposed as the most promising avenue to bridge the gap between biomechanical knowledge and clinical translation, ultimately moving beyond the oversimplified single-axis model in the management of ankle pathology.

Targeting iron-dependent ferroptosis represents a promising strategy to limit myocardial infarction (MI) injury. Wang et al. recently demonstrated that silencing the circadian receptor NR1D2 (REV-ERBβ) preserves ischemic myocardium by activating the Nrf2/GPX4 antioxidant axis. While their mechanistic rigor is commendable, translating NR1D2 modulation to the clinic reveals a pharmacological paradox. Prior studies show that NR1D2 agonists also prevent post-MI heart failure via metabolic remodeling, contrasting with the benefits of NR1D2 inhibition reported here. We argue this discrepancy hinges on temporal specificity: acute knockdown likely halts immediate ferroptotic damage and subsequent DAMP-driven sterile inflammation, whereas subacute agonism supports metabolic recovery. Moving beyond the bench, systemic Nrf2 hyperactivation poses oncogenic risks, and compensatory NR1D1 upregulation may undermine long-term efficacy. Consequently, realizing the therapeutic potential of the NR1D2/Nrf2 axis requires mapping its dynamic post-MI expression to define exact intervention windows, alongside engineering cardiac-homing nanocarriers to bypass systemic toxicity and ensure precise myocardial salvage.

High tibial osteotomy is a key option for patients with unicompartmental overload or instability. Although coronal correction for varus deformity is well established, excessive posterior tibial slope (PTS) is increasingly recognized as a contributor to anterior cruciate ligament graft failure. Conventional strategies often require staged procedures, potentially delaying recovery and compromising bone stock. The "9/9 osteotomy" allows simultaneous correction of varus and excessive PTS in a single stage. The technique combines a lateral closing wedge osteotomy with an anterior retrotubercle closing maneuver. Preoperative planning uses long-leg standing and lateral radiographs to determine mechanical axis, medial proximal tibial angle, and PTS, which guide wedge dimensions and hinge position. Through a lateral approach, a lateral closing wedge is created toward a posteromedial hinge, followed by removal of an anterior wedge behind the tibial tubercle to decrease PTS. Fixation is performed with a lateral locking plate. The 9/9 osteotomy offers a reproducible single-stage solution for combined varus and excessive PTS, preserving bone stock and facilitating early rehabilitation.

Retinoic acid receptor-related orphan receptor beta (RORβ) is a transcription factor expressed in the central nervous system, retina, and bone that regulates circadian rhythms, retinal neurogenesis, and inflammatory signaling. Despite these critical functions, the mechanisms governing RORβ stability remain poorly understood. Here, we identify a post-translational regulatory axis in which the lysine acetyltransferase p300 and the NAD[+]-dependent deacetylase SIRT1 control RORβ stability and transcriptional activity. p300-mediated acetylation increases RORβ abundance, while SIRT1 modulates turnover through both catalytic and non-catalytic scaffolding mechanisms. K176 acetylation in the hinge primes UBC9/PIAS1-mediated SUMOylation at nearby K179, marking RORβ for proteasomal degradation and reducing transcriptional output, providing a mechanistic framework for targeting RORβ in neurological and retinal disorders, and bone homeostasis.

Exposure to environmental pollutants is intimately linked to the onset and progression of chronic liver disease; however, its quantitative contribution to disease burden remains inadequately defined. Although most existing studies concentrate on individual toxicants or discrete signaling pathways, they often fail to elucidate the dynamic transition from early adaptive responses to chronic pathological transformation. Synthesizing current evidence, this review integrates multilevel mechanisms to construct a conceptual framework for continuous pathological progression. We define environmental hepatotoxicity as a dynamic continuum encompassing sequential stages, from adaptive imbalance to chronic pathological advancement. Within this framework, distinct environmental exposures exert dominant effects at specific stages, dictated by their unique molecular response profiles. Individual heterogeneity modulates the trajectory of chronic progression by altering stress tolerance thresholds and systemic homeostatic remodeling. Building on this model, we propose a stage-oriented intervention paradigm that shifts strategically from augmenting adaptive capacity to arresting injury amplification and ultimately reconstructing systemic homeostasis. This framework provides a theoretical scaffold for integrating exposomics with mechanistic research; nevertheless, clinical translation hinges on quantifying low-dose exposure thresholds, identifying dominant factors in combined exposures, and developing stage-specific biomarkers.