Breast cancer metastasis claims the majority of breast cancer-related deaths. Anoikis resistance is a key prerequisite for CTCs survival and metastasis. Previous studies have demonstrated that Nicotinamide N-methyltransferase (NNMT) plays a crucial role in cancer metastasis and apoptosis resistance. However, whether NNMT participates in breast cancer CTCs anoikis remains unexplored. In this study, the upregulation of NNMT was observed in CTCs from breast cancer patients and mouse CTCs models. NNMT in detached breast cancer cells is induced by FAK-STAT3 axis and resists anoikis through FAO activation, promoting CTCs survival. Mechanistically, NNMT promotes the expression of CPT1A and CD36 by suppressing PP2A methylation to enhance FAO. Furthermore, NNMT-induced FAO accelerates ROS clearance by maintaining NADP+/NADPH balance. In vivo experiments show that NNMT-knockdown, NNMT inhibitors and FAO inhibitors can all reduce lung metastases formation, suggesting that targeting NNMT-FAO suppresses the metastatic potential of breast cancer. Our study revealed that the upregulation of NNMT is induced by FAK-STAT3 axis, which contributes to CTCs anoikis resistance in breast cancer by activating FAO. Targeting NNMT may provide new therapeutic targets for metastatic breast cancer.

A nonlinear dynamic model is developed for an uncertain rotor-casing-pedestal coupled system under maneuvering flight. The model incorporates maneuver-induced inertial excitation, blade-casing rub-impact with circumferentially non-uniform clearance, squeeze-film-damper oil-film force, and bounded parameter uncertainties within a unified framework. An interval-based approach combined with Chebyshev polynomial approximation is employed as a computational tool to quantify the dispersion of nonlinear responses induced by parameter uncertainty. Based on the proposed model, the coupled effects of maneuvering motion, non-uniform clearance, and parameter uncertainty on the coupled system dynamics are investigated numerically. The results show that maneuvering flight significantly changes the nonlinear response characteristics of the coupled system, including the bifurcation distribution, transient displacement response, rub-impact force, and steady-state whirling orbit. Circumferentially non-uniform clearance strongly affects the spatial distribution and temporal characteristics of rub-impact, while increasing the number of non-uniform clearance sectors leads to more complex orbit patterns and more frequent contact events. Parameter uncertainty further enlarges the response range of the coupled system; among the considered uncertainties, disc unbalance eccentricity produces a relatively broad response interval over a wide speed range, whereas initial blade-tip clearance causes the most pronounced enlargement in the rub-impact-dominated region. Moreover, maneuver-induced nonlinearity increases the sensitivity of the response to clearance variation and parameter uncertainty. These results provide useful insight into the nonlinear vibration response and rub-impact risk of aero-engine rotor systems under uncertain maneuvering conditions.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKKβ-NF-κB pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKKβ has been limited by serious toxicities, including neutrophilia. Here we identify IKKβ and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKKβ and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKKβ and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrol's ability to bind both IKKβ and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKKβ and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKKβ and NR4A1 as a promising therapeutic strategy.

Abstract Therapy-induced senescence (TIS) occurs following cytotoxic stress and has previously shown to promote tumor metastasis through senescence-associated secretory phenotype (SASP) of stromal cells in the tumor microenvironment, however, whether senescent cancer cells directly participate in metastatic dissemination remains unclear. Here, we report that therapy-induced senescent breast cancer cells actively promote metastatic seeding by physically adhering to parental breast cancer cells and forming circulating senescent-parental cell clusters. Senescence was induced in MDA-MB-231 cells with doxorubicin (39 nM, 7 days) or in 4T1 cells via irradiation (50 Gy, 7 days) and confirmed by X-gal staining, NIR-BG2 senescence probe activity, and increased p16 and SASP expression. RNA-seq revealed upregulation of migration, motility, and adhesion pathways of senescence cells with specific increases in ICAM1, JUP, CLDN1, and CLDN7. Functionally, senescent cells were able to migrate independently, but the presence of both senescent and parental cells in co-culture significantly enhanced migration of both cell types in trans-well and wound healing assays. Hanging-drop aggregation produced large mixed clusters in co-culture, whereas parental cells alone formed scattered microcolonies. Direct adhesion assays showed parental tumor cells preferentially attached to senescent cells versus the substrate, with individual senescent cells binding multiple parental cells. In vivo, orthotopic co-injection of senescent and parental MDA-MB-231 cells in NSG mice resulted in significantly increased lung metastasis. Early tail-vain tracking revealed greater initial lung seeding when co-injected parental cancer cells with senescent MDA-MB-231 in NSG mice and 4T1 cells in NSG and BALB/c mice models, respectively. Interestingly, in immune competent BALB/c mice, metastatic progression sustained over time. These findings reveal a previously unrecognized mechanism in which senescent cancer cells cooperate with parental cancer cells through cell-cell adhesion mediated clustering to facilitate early metastatic colonization. Ongoing studies examine the functional role of ICAM1 and JUP, and the involvement of the immune system as a second phase of metastasis following dissemination, where senescent cells may reshape the microenvironment to promote tumor cells survival. These results suggest that targeting senescent cell adhesion and immune programs may suppress early dissemination and metastatic relapse following cancer therapy. Citation Format: Seyedehalaleh Anvar, Chandra Maharjan, Zixin Chen, Johnathan D Somers, Zeng Jin, Heather R Kates, Servio H. Ramirez, Allison M. Andrews, Breanna M. Runyon, Madison Elizabeth Carelock, Yuzhao Zhang, Jun Liu, Weizhou Zhang, Lina Cui. Senescent cancer cells facilitate metastasis by adhesion-mediated clustering and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4087.

A blade-disk (i.e. blisk) system incorporating self-rotating and whirling effects based on the floating frame of reference formulation is developed using the finite element method. To validate the improved model (IM), static, modal, and transient analyses are successively carried out, and the results are compared with those from the large rotation model (LRM), traditional model I (TM-I), and traditional model II (TM-II). Particularly, the Craig-Bampton method is utilized to reduce the IM. The results show that: (1) LRM, IM, TM-I, and TM-II are reliable for static deformation evaluation; (2) LRM can predict certain eigenfrequencies accurately, while IM is the best for the whole modal property assessment; (3) IM and LRM have high accuracy for disk center and blade tip vibration response, but blade tip response prediction needs attention when using TM-I and TM-II.

Abstract Clear cell renal cell carcinoma (ccRCC) is an aging-associated malignancy characterized by a highly immunosuppressive, immune-rich tumor microenvironment and variable response to immune checkpoint blockade. Regulatory T cells (Tregs) are dominant orchestrators of immune suppression in ccRCC, yet the functional consequences of cellular senescence in these cells remain unknown and are widely presumed to be impairing. Single-cell RNA sequencing of treatment-naïve human ccRCC tumors revealed a distinct tumor-infiltrating Treg (TI-Treg) subpopulation co-expressing classic senescence markers (p16^INK4a, p21), senescence-associated β-galactosidase activity (SA-β-gal), BCL-xL, and robust immunosuppressive effector programs. Contrary to the prevailing view that senescence attenuates Treg function, we hypothesized that senescent TI-Tregs retain potent suppressive capacity. To functionally characterize these senescent TI-Treg subsets, we used a novel activity-based fluorescent senescence probe that labels SA-β-gal and employed p16-tdTomato reporter mice for the isolation of viable senescent TI-Tregs. Additionally, using an in vitro co-culture system in which naïve Tregs are driven into senescence by ccRCC cell-derived factors, suppression assays demonstrated that senescent Tregs maintain strong inhibitory activity against CD4+ T-cell proliferation, comparable to non-senescent Tregs. Concomitant RNA sequencing confirmed persistence of canonical immunosuppressive pathways and acquisition of a senescence-reinforced suppressive transcriptome. These findings challenge the assumptions that senescence Tregs are dysfunctional in cancer and establish senescent Tregs as critical contributors to immunosuppression in aging-associated ccRCC. This work unravels senescent TI-Tregs as therapeutic targets/vulnerabilities for their selective elimination to restore antitumor immunity. Citation Format: Temitope Mary Ogunmola, Myung-Chul Kim, Zeng Jin, Umasankar de, Lina Cui, Guangrong Zheng, Ryan Kolb, Weizhou Zhang. Senescent regulatory T cells retain potent suppressive function in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7398.

While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. BNIP3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, BNIP3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.

Acute myeloid leukemia (AML) is a common and aggressive blood cancer with the highest lethality rate among all leukemia subtypes. The cure rate of available therapeutic options is very low, underscoring an urgent need to develop novel and effective AML therapeutics. Here we identify IKKβ and NR4A1 as two closely related drivers of AML progression and develop a proteolysis targeting chimera (PROTAC) drug that has dual degradation activity against IKKβ and NR4A1. IKKβ and its downstream nuclear factor-κB (NF-κB) signaling are aberrantly activated in around 40% AML patients. However, nearly all IKKβ inhibitors have failed prior clinical trials due to their serious side effects such as neutrophilia and systematic inflammation. As opposed to the previously reported tumor suppressive role in AML, we found that NR4A1 promotes AML pathogenesis in a context-dependent manner. Here we designed, synthesized, and validated several celastrol-based PROTACs, with one lead compound A9 that effectively kills several AML cell lines and primary human AML cells via the degradation of IKKβ and NR4A1. At the mechanistic level, A9 degrades both targets through cereblon (CRBN) E3 ligase-mediated proteasomal system by forming ternary complexes with the target proteins and CRBN. More importantly, A9 attenuates AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and doesn't induce neutrophilia in vivo - a common side effect of IKKβ inhibitors. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic. Key Points:IKKβ and NR4A1 are clinically relevant mediators of AML pathogenesis.A novel celastrol-based PROTAC can effectively degrade both IKKβ and NR4A1 to disrupt AML pathogenesis.

This paper aims to study the steady-state response intervals in an uncertain double-span rotor system subjected to model uncertainty. Firstly, the mathematical modelling of the deterministic dynamical system is carried out based on the Lagrangian formulation. The impact force and frictional force are described by the Lankarani-Nikravesh model and Coulomb model, respectively. Subsequently, a nonparametric dynamical model incorporating Random Matrix Theory (RMT) and Maximum Entropy Principle (MEP) is further derived. The random matrices of the system are solved via polar decomposition of matrices. Then the nonparametric uncertainty is characterized by the dispersion parameter identification method, and the accuracy of this method is validated through frequency-sweep experiment performed on a rotor test rig. Through numerical calculation, the lower and upper bounds of the dynamic characteristics in the nonparametric uncertain rotor system are investigated in detail. Meanwhile, a comparative study on the dynamic responses of deterministic rotor and uncertain rotor is conducted under the conditions of with and without rub-impact. The results can offer technical guidance for the dynamic analysis and fault diagnosis of rotor systems under model uncertainty.

[This corrects the article DOI: 10.1016/j.bioactmat.2025.08.029.].

In this paper, the geometrically exact beam theory (GEBT) and blade element momentum theory (BEMT) are used to establish the aeroelastic coupling model for analyzing the dynamics of flexible icing wind turbine blades. The developed model is verified by several examples. Besides, three nonuniform wind inflow modes are introduced in this paper. Then, the effects of icing mass and icing aerodynamics are studied respectively, and the simulation results show that the mass and aerodynamic effects of icing have different influences on blades. Next, the electromechanical characteristics of icing blades under three nonuniform wind inflow modes are calculated and analyzed respectively, and the dynamic responses under different pitch angles are compared. Furthermore, to obtain the dynamic characteristics of icing blades as closely as possible to the actual operation conditions, the case of icing blades under above factors simultaneously is simulated and analyzed. Finally, the several main conclusions of icing blades are summarized.

To achieve high thrust-to-weight ratio and high efficiency, aero-engines generally adopt the dual-rotor structure design. Among them, due to design dispersion, assembly errors and long-term service, various uncertainties exist throughout the entire service process of dual-rotor systems. Under this circumstance, due to small size design of blade tip clearance, the uncertainties further have a potential influence on the rub-impact fault, which poses greater challenges to the evaluation of dynamic characteristics. This paper aims to investigate the vibration steady-state behaviors of a non-probabilistic uncertain dual-rotor system with/without rub-impact fault between turbine blades and casings. Then the governing equations of motion of deterministic dual-rotor system with rub-impact are theoretical derived based on the finite element theory. The effects of individual uncertain parameters and combinations of multiple uncertain parameters are described by the Chebyshev interval algorithm. After that the response comparisons between deterministic system and uncertain system are conducted at different rotational speeds. Besides, the rub response intervals of dual-rotor system are further determined in terms of time histories, whirling orbit, and impact force. Through sensitivity analysis, the sensitive parameters for the dual-rotor system are further clarified as well. Finally, to verify the effectiveness of theoretical analysis, the beat vibration experiment is performed on a dual-rotor test rig, which proves that the experimental results are exactly within the range of uncertain response intervals.

Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in pre-metastatic niches, their effector functions in eliminating disseminated tumor cells, and their dynamic crosstalk with local stromal and myeloid populations. Here, we highlight evidence for organ-specific variability in TRM cell-mediated immunity, discuss strategies for therapeutically harnessing these cells—ranging from vaccination and checkpoint modulation to chemokine axis manipulation—and explore their promise as prognostic biomarkers. Finally, we outline key knowledge gaps and future directions aimed at translating TRM cell biology into targeted interventions to prevent and treat metastatic disease.

In this paper, the time-varying mesh stiffness (TVMS) of a gear is meticulously derived using the potential energy method (PEM) and an analytical expression for it is obtained. Subsequently, calculations are performed to determine the effects of crack depth and crack angle on the TVMS. The validation is carried out using the finite element method (FEM). Then, a discussion is carried out on the dynamic characteristics of a spur gear system with a crack. Moreover, uncertainty is an objective reality in gear systems, arising from various factors such as the material properties and working environment. To enable a more reasonable evaluation of the dynamic characteristics of the spur gear system, this paper presents a deviation of an uncertainty interval analysis method based on Chebyshev polynomials. A dynamic model of the spur gear system with uncertain parameters is then proposed. The dynamic response of a gear transmission system with these uncertain parameters is investigated in detail. Additionally, the interval response of a gear system with root cracks under uncertainty is further investigated. The experimental results confirm the inherent presence of uncertainty in the gear system and validate the effectiveness of the proposed uncertainty analysis method.

Orphan nuclear receptor 4A1 (NR4A1, Nur77) plays a crucial role in regulating immune cell metabolism and function within the tumor microenvironment (TME), thus influencing cancer progression and serving as a potential therapeutic target for cancer immunotherapy. A comprehensive review discussing the multifaceted roles of NR4A1 in immune cells and the exploitation of that knowledge for therapeutic development is lacking in the field. This review explores diverse functions of NR4A1 in tumor-associated immune cells, including T cells, monocytes, natural killer cells, B cells, dendritic cells, macrophages, and neutrophils. NR4A1 contributes to immune regulation by impacting cytokine production, cell differentiation, and immune cell exhaustion. We highlight how NR4A1 in immune cells within the TME may be either a positive (e.g., macrophages in colon cancer) or negative prognostic factor (e.g., T cells in melanoma), depending on the cancer and immune cell context. Additionally, this review also highlights potential therapeutic strategies targeting NR4A1, leading to its inhibition, activation, or degradation to restore immune cell function and enhance anti-tumor immunity. Such therapies could potentially improve patient outcomes by altering immune cell behaviors, blocking intrinsic tumor growth pathways, or via both mechanisms. However, the development of NR4A1-targeted therapies will be dependent on further research to better understand lineage-specific roles of NR4A1 and the underlying mechanisms across different cancer types and immune cells.

Abstract B-cell lymphoma X-large (BCL-XL) emerges as a significant player in cancer progression. In our recent findings, we unveil the efficacy of proteolysis-targeting chimeras (PROTACs) directed against BCL-XL, demonstrating their capacity to not only eliminate cancer cells but also target tumor-induced regulatory T cells (TI-Tregs). Notably, BCL-XL's role in promoting breast cancer metastasis extends beyond its anti-apoptotic function. We posit that BCL-XL-targeting PROTACs (BCL-XL-Ps) hold promise for treating metastatic breast cancer. Their potential lies in directly eliminating circulating tumor cells during vulnerable stages and/or triggering anti-cancer immunity through Treg cell depletion. Our experiments underscore the potency of IAP-based PROTACs in facilitating BCL-XL degradation via the ubiquitin-proteasome system (UPS) while mitigating on-target platelet toxicity. Treatment of breast cancer-bearing mice with these compounds demonstrates a tangible reduction in breast cancer metastasis to the lungs. Additionally, our studies reveal a significant depletion of tumor-infiltrating Tregs in mice treated with BCL-XL-Ps. While affirming BCL-XL as a viable therapeutic target for breast cancer metastasis, further exploration into the mechanisms behind BCL-XL-P targeting is imperative. Our future endeavors will be devoted to unraveling whether our BCL-XL-Ps effectively target both tumor-intrinsic BCL-XL, potentially inducing tumor cell death, and tumor-infiltrating Tregs, thereby fostering an adaptive immune response against the tumor cells. Citation Format: Madison E. Carelock, Peiyi Zhang, Mo Jiao, Umasankar De, Zeng Jin, Rachel M. Stump, Sarah G. Williams, Guangrong Zheng, Weizhou Zhang. Attenuating breast cancer metastasis with BCL-XL-targeting PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4123.

The operation of an aero-engine involves various non-stationary processes of acceleration and deceleration, with rotational speed varying in response to changing working conditions to meet different power requirements. To investigate the nonlinear dynamic behaviour of cracked blades under variable rotational speed conditions, this study constructed a rotating blade model with edge-penetrating cracks and proposes a component modal synthesis method that accounts for time-varying rotational speed. The nonlinear response behaviours of cracked blades were examined under three distinct operating conditions: spinless, steady speed, and non-constant speed. The findings indicated a competitive relationship between the effects of rotational speed fluctuations and unbalanced excitation on crack nonlinearity. Variations in rotational speed dominated when rotational speed perturbation was minimal; conversely, aerodynamic forces dominated when the effects of rotational speed were pronounced. An increase in rotational speed perturbation enhanced the super-harmonic nonlinearity induced by cracks, elevated the nonlinear damage index (NDI), and accentuated the crack breathing effect. As the perturbation coefficient increased, the super-harmonic nonlinearity of the crack intensified, resulting in a more complex vibration form and phase diagram.

As an important pipeline support component, metal rubber clamp is mainly used for pipeline connection, fixation and vibration isolation. At present, the researches on hysteretic and stiffness characteristics of metal rubber clamps in aero engines are still in their infancy. This work aims to develop a nonlinear mechanical calculation model for metal rubber clamps to effectively capture the nonlinear mechanical properties, such as hysteresis characteristics and variable stiffness behavior. The equivalent stiffness model of metal rubber clamps was established by introducing tightening torque and friction between metal wires as control variables, and the mechanical behavior under repeated loads is analyzed by combining the force and deformation relations of typical hysteretic curves. By comparing the measured hysteretic curve and natural frequencies, the proposed equivalent stiffness model of a metal rubber clamp is verified. This also suggests that the proposed model can effectively simulate the dry friction damping characteristics of metal rubber. In addition, the effects of tightening torque and friction coefficient on hysteretic characteristics and stiffness are also analyzed. The aim of this study is to develop mechanical anisotropy tests integrated with equivalent numerical simulation techniques to elucidate the mechanical characteristics of the aero engine clamp. The research can provide theoretical support for the structural design of metal rubber clamps.