Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells.

Stem cells respond and remember mechanical cues from the microenvironment, which modulates their therapeutic effects. Chromatin organization and energy metabolism regulate the stem cell fate induced by mechanical cues. However, the mechanism of mechanical memory is still unclear. This study aimed to investigate the effects of mechanical amplitude, frequency, duration, and stretch cycle on mechanical memory in mesenchymal stem cells. It showed that the amplitude was the dominant parameter to the persistence of cell alignment. F-actin, paxillin, and nuclear deformation are more prone to be remolded than cell alignment. Stretching induces transcriptional memory, resulting in greater transcription upon subsequent reloading. Cell metabolism displays mechanical memory with sustained mitochondrial fusion and increased ATP production. The mechanical memory of chromatin condensation is mediated by histone H3 lysine 27 trimethylation, leading to much higher smooth muscle differentiation efficiency. Interestingly, mechanical memory can be transmitted based on direct cell-cell interaction, and stretched cells can remodel the metabolic homeostasis of static cells. Our results provide insight into the underlying mechanism of mechanical memory and its potential benefits for stem cell therapy.

Kinematic difference and asymmetries during level walking in adolescent patients with different types of mild scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS), three-dimensional spine deformation, affects body motion. Previous research had indicated pathological gait patterns of AIS. However, the impact of the curve number on the walking mechanism has not been established. Therefore, this study aimed to compare the gait symmetry and kinematics in AIS patients with different curve numbers to healthy control. RESULTS: In the spinal region, double curves AIS patients demonstrated a smaller sagittal symmetry angle (SA) and larger sagittal convex ROM of the trunk and lower spine than the control group. In the lower extremities, the single curve patients showed a significantly reduced SA of the knee joint in the frontal plane, while the double curves patients showed a significantly reduced SA of the hip in the transverse plane. CONCLUSION: The curve number indeed affects gait symmetry and kinematics in AIS patients. The double curves patients seemed to adopt a more "careful walking" strategy to compensate for the effect of spinal deformation on sensory integration deficits. This compensation mainly occurred in the sagittal plane. Compared to double curves patients, single curve patients unitized a similar walking strategy with healthy subjects.

Reconstruction Strategy for Upper Extremity Defects After Bone Tumor Resection Based on 3D Customized Bone Cement Mold.

BACKGROUND: Reconstructing bone defects in the upper extremities and restoring their functions poses a significant challenge. In this study, we describe a novel workflow for designing and manufacturing customized bone cement molds using 3D printing technology to reconstruct upper extremity defects after bone tumor resection. METHODS: Computer tomography data was acquired from the unaffected upper extremities to create a detachable mold, which can be customized to fit the joint precisely by shaping the bone cement accordingly. Fourteen patients who underwent reconstructive surgery following bone tumor resection in the proximal humerus (13 cases) or distal radius (1 case) between January 2014 and December 2022 were retrospectively evaluated. The medical records of this case series were reviewed for the demographic, radiological, and operative data. Metastasis, local recurrence, and complication were also reviewed. Additionally, Musculoskeletal Tumor Society Score (MSTS) and Visual Analogue Scale (VAS) were used to assess clinical outcomes. RESULTS: The mean follow-up period was 49.36 ± 15.18 months (range, 27-82 months). At the end of follow-up, there were no cases of metastasis or recurrence, and patients did not experience complications such as infection, dislocation, or implant loosening. Two cases complicated with subluxation (14.3%), and 1 case underwent revision surgery for prosthetic fracture (7.1%). The average MSTS score was 23.2 ± 1.76 (77.4%, range, 66.7%-86.7%), and the postoperative VAS score was 1.86 ± 1.03 (range, 1-4), which was significantly lower than that before surgery (average preoperative VAS score was 5.21 ± 2.00 (range, 2-8)) (P < .001). CONCLUSION: Customized 3D molds can be utilized to shape bone cement prostheses, which may serve as a potential alternative for reconstructing the proximal humerus and distal radius following en bloc resection of bone tumors. This reconstruction strategy offers apparent advantages, including precise matching of articular surfaces and comparatively reduced costs.

Comparative assessment of orthodontic clear aligner versus fixed appliance for anterior retraction: a finite element study.

BACKGROUND: The aim of this study is to conduct a comparative evaluation of different designs of clear aligners and examine the disparities between clear aligners and fixed appliances. METHODS: 3D digital models were created, consisting of a maxillary dentition without first premolars, maxilla, periodontal ligaments, attachments, micro-implant, 3D printed lingual retractor, brackets, archwire and clear aligner. The study involved the creation of five design models for clear aligner maxillary anterior internal retraction and one design model for fixed appliance maxillary anterior internal retraction, which were subsequently subjected to finite element analysis. These design models included: (1) Model C0 Control, (2) Model C1 Posterior Micro-implant, (3) Model C2 Anterior Micro-implant, (4) Model C3 Palatal Plate, (5) Model C4 Lingual Retractor, and (6) Model F0 Fixed Appliance. RESULTS: In the clear aligner models, a consistent pattern of tooth movement was observed. Notably, among all tested models, the modified clear aligner Model C3 exhibited the smallest differences in sagittal displacement of the crown-root of the central incisor, vertical displacement of the central incisor, sagittal displacement of the second premolar and second molar, as well as vertical displacement of posterior teeth. However, distinct variations in tooth movement trends were observed between the clear aligner models and the fixed appliance model. Furthermore, compared to the fixed appliance model, significant increases in tooth displacement were achieved with the use of clear aligner models. CONCLUSIONS: In the clear aligner models, the movement trend of the teeth remained consistent, but there were variations in the amount of tooth displacement. Overall, the Model C3 exhibited better torque control and provided greater protection for posterior anchorage teeth compared to the other four clear aligner models. On the other hand, the fixed appliance model provides superior anterior torque control and better protection of the posterior anchorage teeth compared to clear aligner models. The clear aligner approach and the fixed appliance approach still exhibit a disparity; nevertheless, this study offers a developmental direction and establishes a theoretical foundation for future non-invasive, aesthetically pleasing, comfortable, and efficient modalities of clear aligner treatment.

Viscoelastic response of gray matter and white matter brain tissues under creep and relaxation.

Accurate measurement of the mechanical properties of brain tissue is of paramount importance for understanding its mechanics-biology relationship. Most published studies on brain viscoelasticity have been conducted using a single relaxation test, without validating the validity of linear viscoelasticity, which is insufficient to establish an accurate constitutive equation for brain tissue. We obtained the creep and relaxation profiles of fresh adult porcine white matter (N = 120) and gray matter (N = 56) under finite step-and-hold uniaxial compression, using a mechanical testing machine, with 16.67 mm/s loading rate and 80 s hold time. These curves were employed to determine viscoelastic properties and demonstrated an excellent fit with a concise power-law function. The average initial modulus for gray matter (GM) was 6.619 kPa, higher than that for white matter under transverse loading (WM-2D) at 5.579 kPa (p < 0.01), yet lower than that for white matter under axial loading (WM-1D) at 6.759 kPa (p = 0.0121). Notably, WM-2D exhibited the highest degree of fluidity (ß = 0.216). Our findings reveal that gray matter behaves as a linear viscoelastic material with power-law creep compliance and relaxation modulus. Conversely, the creep and relaxation behavior of white matter deviates from the verification relationship derived from linear viscoelastic theory, indicating its nonlinearity. This fact underscores the inaccuracy of assuming a linear constitutive relationship to characterize the viscoelastic properties of white matter. By combining the power-law function with the experimentally obtained creep compliance and relaxation modulus, we offer a unique approach to determining the viscoelastic characteristics of brain tissue.

In Silico: Predicting Intrinsic Features of HLA Class-I Restricted Neoantigens.

Mutation-containing immunogenic peptides from tumor cells, also named as neoantigens, have various amino acid descriptors and physical-chemical properties characterized intrinsic features, which are useful in prioritizing the immunogenicity potentials of neoantigens and predicting patients' survival. Here, we describe a glioma neoantigen intrinsic feature database, GNIFdb, that hosts computationally predicted HLA-I restricted neoantigens of gliomas, their intrinsic features, and the tools for calculating intrinsic features and predicting overall survival of gliomas. We illustrate the application of GNIFdb in searching for possible neoantigen candidates from ATF6 that plays important roles in tumor growth and resistance to radiotherapy in glioblastoma. We also demonstrate the application of intrinsic feature associated tools in GNIFdb to predict the overall survival of primary IDH wild-type glioblastoma.

Multi-Method Investigation of Blood Damage Induced By Blood Pumps in Different Clinical Support Modes.

To investigate the effects of blood pumps operated in different modes on nonphysiologic flow patterns, cell and protein function, and the risk of bleeding, thrombosis, and hemolysis, an extracorporeal blood pump (CentriMag) was operated in three clinical modalities including heart failure (HF), venous-venous (V-V) extracorporeal membrane oxygenation (ECMO), and venous-arterial (V-A) ECMO. Computational fluid dynamics (CFD) methods and coupled hemolysis models as well as recently developed bleeding and thrombosis models associated with changes in platelet and von Willebrand factor (vWF) function were used to predict hydraulic performance and hemocompatibility. The V-A ECMO mode had the highest flow losses and shear stress levels, the V-V ECMO mode was intermediate, and the HF mode was the lowest. Different nonphysiologic flow patterns altered cell/protein morphology and function. The V-A ECMO mode resulted in the highest levels of platelet activation, receptor shedding, vWF unfolding, and high molecular weight multimers vWF (HMWM-vWF) degradation, leading to the lowest platelet adhesion and the highest vWF binding capacity, intermediate in the V-V ECMO mode, and opposite in the HF mode. The V-A ECMO mode resulted in the highest risk of bleeding, thrombosis, and hemolysis, with the V-V ECMO mode intermediate and the HF mode lowest. These findings are supported by published experimental or clinical statistics. Further studies found that secondary blood flow passages resulted in the highest risk of blood damage. Nonphysiologic blood flow patterns were strongly associated with cell and protein function changing, blood damage, and complications.

Construction of chitosan-gelatin polysaccharide-protein composite hydrogel via mechanical stretching and its biocompatibility in vivo.

Natural polysaccharides and protein macromolecules are the important components of extracellular matrix (ECM), but individual component generally exhibits weak mechanical property, limited biological function or strong immunogenicity in tissue engineering. Herein, gelatin (Gel) was deposited to the stretched (65 %) chitosan (CS) hydrogel substrates to fabricate the polysaccharide-protein CS-Gel-65 % composite hydrogels to mimic the natural component of ECM and improve the above deficiencies. CS hydrogel substrates under different stretching deformations exhibited tunable morphology, chemical property and wettability, having a vital influence on the secondary structures of deposited fibrous Gel protein, namely appearing with the decreased ß-sheet content in stretched CS hydrogel. Gel also produced a more homogenous distribution on the stretched CS hydrogel substrate due to the unfolding of Gel and increased interactions between Gel and CS than on the unstretched substrate. Moreover, the polysaccharide-protein composite hydrogel possessed enhanced mechanical property and oriented structure via stretching-drying method. Besides, in vivo subcutaneous implantation indicated that the CS-Gel-65 % composite hydrogel showed lower immunogenicity, thinner fibrous capsule, better angiogenesis effect and increased M2/M1 of macrophage phenotype. Polysaccharide-protein CS-Gel-65 % composite hydrogel offers a novel material as a tissue engineering scaffold, which could promote angiogenesis and build a good immune microenvironment for the damaged tissue repair.

A Shape Memory Polymeric Shield for Protecting Corneal Endothelium During Phacoemulsification.

Background: The purpose of this study was to explore the protective effect of a shape memory polymeric shield on corneal endothelium during phacoemulsification in rabbits. Methods: Poly-(glycerol dodecanedioate) (PGD) with a transition temperature of 24.416°C was prepared to make a shape memory shield with a thickness of 100 µm, an arc length of 14 mm, and a radius of curvature of 8.8 mm. In the control group, a phaco-tip with bevel-down was used to simulate injury to the corneal endothelium by phacoemulsification in rabbits. In the experimental group, the pre-cooled and curled shape memory shield was injected into and removed from the anterior chamber before and after phaco-power release. Anterior segment optical coherence tomography (AS-OCT), confocal microscope, trypan blue/alizarin red staining, and scanning electron microscope were performed to measure endothelial damage after surgery. Results: One day postoperatively, the lost cell ratio of the control group and the experimental group were 28.08 ± 5.21% and 3.50 ± 1.43%, respectively (P < 0.0001), the damaged cell ratios were 11.83 ± 2.30% and 2.55 ± 0.52%, respectively (P < 0.0001), and the central corneal thicknesses (CCT) were 406.75 ± 16.74 µm and 340. 5 ±13.48 µm, respectively (P < 0.0001). Seven days postoperatively, the endothelial cell density (ECD) of the control group and the experimental group were 1674 ± 285/mm2 and 2561 ± 554/mm2, respectively (P < 0.05). The above differences were all statistically significant. Conclusions: This PGD based shape memory shield has a protective effect on corneal endothelium during phacoemulsification. It reduces postoperative corneal edema and ECD decrease in the short term after surgery. Translational Relevance: The shape memory PGD "shield" in this study may have a use in certain human patients with vulnerable corneas of low endothelial cell count or shallow anterior chambers.

Symmetrical structure design of PLGA Biodegradable sinus stents and structure optimization based on surrogate models.

This study aims to enhance the degradation uniformity of PLGA sinus stents to minimize fracture risk caused by stress corrosion. Symmetric stent structures were introduced and compared to sinusoidal structure in terms of stress and degradation uniformity during implantation and degradation processes. Three surrogate models were employed to optimize the honeycomb-like structure. Results showed honeycomb-like structures exhibited the superior stress distribution and highest degradation uniformity. The kriging model achieved the smallest error and degradation uniformity of 83.24%. In conclusion, enhancing the symmetry of stent structures improves degradation uniformity, and the kriging model has potential for the optimization of stent structures.

Structural optimization of degradable polymer vascular stents based on surrogate models.

The clinical performance of biodegradable polymer stents implanted in blood vessels is affected by uneven degradation. Stress distribution plays an important role in polymer degradation, and local stress concentration leads to the premature fracture of stents. Numerical simulations combined with in vitro experimental validation can accurately describe the degradation process and perform structural optimization. Compared with traditional design techniques, optimization based on surrogate models is more scientifically effective. Three stent structures were designed and optimized, with the effective working time during degradation as the optimization goal. The finite element method was employed to simulate the degradation process of the stent. Surrogate models were employed to establish the functional relationship between the design parameters and the degradation performance. The proposed function models accurately predicted the degradation performance of various stents. The optimized stent structures demonstrated improved degradation performance, with the kriging model showing a better optimization effect. This study provided a novel approach for optimizing the structural design of biodegradable polymer stents to enhance degradation performance.

Lateralization of cortical activity, networks, and hemodynamic lag after stroke: A resting-state fNIRS study.

Focal damage due to stroke causes widespread abnormal changes in brain function and hemispheric asymmetry. In this study, functional near-infrared spectroscopy (fNIRS) was used to collect resting-state hemoglobin data from 85 patients with subacute stroke and 26 healthy controls, to comparatively analyze the characteristics of lateralization after stroke in terms of cortical activity, functional networks, and hemodynamic lags. Higher intensity of motor cortical activity, lower hemispheric autonomy, and more abnormal hemodynamic leads or lags were found in the affected hemisphere. Lateralization metrics of the three aspects were all associated with the Fugl-Meyer score. The results of this study prove that three lateralization metrics may provide clinical reference for stroke rehabilitation. Meanwhile, the present study piloted the use of resting-state fNIRS for analyzing hemodynamic lag, demonstrating the potential of fNIRS to assess hemodynamic abnormalities in addition to the study of cortical neurological function after stroke.

The study of loading mode with in-vitro fatigue testing for mitral annuloplasty ring.

To maintain the physiological dynamics of the mitral annulus, mitral annuloplasty rings (MAR) must be flexible. Enhanced flexibility implies decreased resistance to fatigue and potential for fatigue fracture. This study established new methods to test the flexible fatigue life of MAR in-vitro using numerical analysis; the purpose is that the fatigue test could reflect the real stress distribution in-vivo. Based on the conventional test methods (C1, D1), this paper presents a novel test method (C2, D2). Four testing methods for open-end annuloplasty rings (C1, C2) and closed-end annuloplasty rings (D1, D2) were modelled and their stress distribution calculated by finite element analysis. The mean absolute error (Χ) and the Pearson correlation coefficient (Φ) were used to quantify the difference in stress distribution between the loading modes in-vivo and in-vitro. For closed-end annuloplasty rings, the novel test method (D2) is not obvious better than conventional test methods(D1) in duplicating the stress distribution (ΦD1 = 0.88 vs ΦD2 = 0.92). However, the maximum values of stress in the novel test method are closer to the maximum value of stress under in-vivo loading (ΧD1 = 5.2Mpa vs ΧD2 = 4.4Mpa). For open-end annuloplasty rings, the novel test method(C2) is obviously superior to the conventional test method(C1) in duplicating both the stress distribution and the stress peak values of the in-vivo loading (ΦC1 = 0.22 vs ΦC2 = 0.98; ΧC1 = 59.1Mpa vs ΧC2 = 11.0Mpa). The in-vitro loading methods described in this article more closely approximated in-vivo conditions compared to traditional methods. They are simpler to operate, more efficient and can help manufacturers expedite new product development, assist regulatory agencies with product quality oversight.

A biomechanical analysis of novel endovascular implants for aortic valve replacement and ascending aortic repair.

Advances in medical technology have enabled minimally invasive treatment of type A aortic dissection with accompanying aortic regurgitation. Implants include endovascular stent grafts (ESG) and heart valve substitute (HVS) modules. Traditional implants can be divided into two types based on the assembly relationship between ESG and HVS: separated z-shaped implants (SZ) and separated diamond-shaped implants (SD). This study proposes a novel linked diamond-shaped implant (LD). To evaluate the safety and effectiveness of this new implant, finite element simulation models were created to assess the risks of endoleak, migration, and vascular wall rupture under annulus displacement load. After the SZ, SD, and LD implants were grafted in virtual release method, all the implants can cover tear-entry located in the ascending aorta, but space distance (δ) which exposed to blood was 14.5, 13.1, and 7.4 mm, respectively; the maximum areas of contact gap was 76.5, 51.5 and 6.3 mm2; the maximum migration distance (ΔL1) were 1.27, 1.06, and 0.1 mm; the maximum stress on ascending aorta was 0.19, 0.24, and 0.51 MPa, which were lower than failure stress (0.9 MPa). This study showed that both SZ and SD implants had minimal effects on the ascending aorta; however, higher risks were associated with implant migration and proximal endoleak. In contrast, the LD implant can simplify the surgical procedure, has a lower risk of endoleak and migration, and limited stress stimulation of the aorta. This study validated the feasibility and effectiveness of this novel implant using the finite element method, indicating its potential as a secure and reliable treatment option.

Enhancing Chronic Wound Healing through Engineering Mg2+-Coordinated Asiatic Acid/Bacterial Cellulose Hybrid Hydrogels.

Infectious chronic wounds have gradually become a major clinical problem due to their high prevalence and poor treatment outcomes. The urgent need for wound dressings with immune modulatory, antibacterial, and angiogenic properties has led to the development of innovative solutions. Asiatic acid (AA), derived from herbs, has demonstrated excellent antibacterial, anti-inflammatory, and angiogenic effects, making it a promising candidate for incorporation into hydrogel carriers for wound healing. However, there is currently no available report on AA-based self-assembled hydrogels. Here, a novel hybrid hydrogel dressing consists of interpenetrating polymer networks composed of self-assembled magnesium ion (Mg2+) coordinated asiatic acid (AA-Mg) and bacterial cellulose (BC) is developed to promote infected chronic wound healing. A natural carrier-free self-assembled AA-Mg hydrogel with good injectable and self-healing properties could maintain the sustained release of AA and Mg2+ over an extended period. Notably, the introduction of Mg2+ boosted some pharmacological effects of self-assembled hydrogels due to its excellent anti-inflammatory and angiogenesis. In vitro studies confirmed the exceptional biocompatibility, antibacterial efficacy, and anti-inflammatory potential of the AA-Mg/BC hybrid hydrogel, which also exhibited a commendable mechanical strength. Furthermore, in vivo biological results displayed that the hybrid hydrogel significantly accelerated the wound healing process by boosting dense and organized collagen deposition and the granulation tissue and benefiting revascularization. The introduced self-assembled AA-Mg-based hydrogel offers a promising solution for the effective management of chronic wounds. This universal strategy for the preparation of self-assembled hydrogels modulated with bioactive divalent metal ions is able to excavate more herbal small molecules to construct new self-assembled biomaterials.

Tolerogenic Nano-/Microparticle Vaccines for Immunotherapy.

Autoimmune diseases, allergies, transplant rejections, generation of antidrug antibodies, and chronic inflammatory diseases have impacted a large group of people across the globe. Conventional treatments and therapies often use systemic or broad immunosuppression with serious efficacy and safety issues. Tolerogenic vaccines represent a concept that has been extended from their traditional immune-modulating function to induction of antigen-specific tolerance through the generation of regulatory T cells. Without impairing immune homeostasis, tolerogenic vaccines dampen inflammation and induce tolerogenic regulation. However, achieving the desired potency of tolerogenic vaccines as preventive and therapeutic modalities calls for precise manipulation of the immune microenvironment and control over the tolerogenic responses against the autoantigens, allergens, and/or alloantigens. Engineered nano-/microparticles possess desirable design features that can bolster targeted immune regulation and enhance the induction of antigen-specific tolerance. Thus, particle-based tolerogenic vaccines hold great promise in clinical translation for future treatment of aforementioned immune disorders. In this review, we highlight the main strategies to employ particles as exciting tolerogenic vaccines, with a focus on the particles' role in facilitating the induction of antigen-specific tolerance. We describe the particle design features that facilitate their usage and discuss the challenges and opportunities for designing next-generation particle-based tolerogenic vaccines with robust efficacy to promote antigen-specific tolerance for immunotherapy.

Optimizing the design of axial flow pump blades based on fluid characteristics.

Non-physiological blood flow conditions in axial blood pumps lead to some complications, including hemolysis, platelet activation, thrombosis, and embolism. The high speed of the axial blood pump destroys large amounts of erythrocytes, thereby causing hemolysis and thrombosis. Thus, this study aims to reduce the vortices and reflux in the flow field by optimizing the axial blood pump. The axial blood pump and arterial flow field were modeled by the finite element method. The blood was assumed to be incompressible, turbulent, and Newtonian. The SST k-ω turbulence model was used. The frozen rotor method was also used to calculate the snapshot of motion. Many vortices and reflux exist in the flow field of the blood pump without optimization. The improved flow field had almost no vortex and reflux, thereby reducing the exposure time of blood. The optimized blood pump had little influence on the pressure field and shear stress field. The optimized blood pump mainly reduced the vortex, reflux, and the risk of thrombosis in the flow field. The flow field characteristics of an axial blood pump were studied, and the results showed the risk of thrombosis and hemolysis in the blood pump. In accordance with the relationship between the blade shape and the flow field, the blade of the blood pump was optimized, reducing the vortex and reflux of the flow field, as well as the risk of thrombosis.

The Impact of Rotor Axial Displacement Variation on Simulation Accuracy of Fully Magnetic Levitation Centrifugal Blood Pump.

The rotor axial displacement of the full magnetic levitation blood pump varies with the operating conditions. The effect of rotor axial displacement on simulation results is unclear. This study aimed to evaluate the effect of rotor axial displacement on the predicted blood pump flow field, hydraulic performance, and hemocompatibility through simulation. This study used the CentriMag blood pump as a model, and conducted computational fluid dynamics simulations to assess the impact of rotor displacement. Considering rotor axial displacement leads to opposite results regarding predicted residence time and thrombotic risk compared with not considering rotor axial displacement. Not considering rotor axial displacement leads to deviations in the predicted values, where the effects on the flow field within the blood pump, ratio of secondary flow, and amount of shear stress >150 Pa are significant. The variation in the back clearance of the blood pump caused by the ideal and actual rotor displacements is the main cause of the above phenomena. Given that the rotor axial displacement significantly impacts the simulation accuracy, the effect of rotor axial displacement must be considered in the simulation.

Synthesis and characterization of 64Cu-labeled Geldanamycin derivative for imaging HSP90 expression in breast cancer.

Heat shock protein 90 (HSP90) plays a crucial role in cancer cell growth and metastasis by stabilizing overexpressed signaling proteins. Inhibiting HSP90 has emerged as a promising anti-cancer strategy. In this study, we aimed to develop and characterize a HSP90-targeted molecular imaging probe, [64Cu]Cu-DOTA-BDA-GM, based on a specific HSP90 inhibitor, geldanamycin (GM), for PET imaging of cancers. GM is modified at the C-17 position with 1,4-butane-diamine (BDA) and linked to 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for 64Cu radiolabeling. We evaluated the probe's specific binding to HSP90-expressing cells using Chinese hamster ovary (CHO) cells and breast cancer cells including MDA-MB-231, MDA-MB-435S, MCF7, and KR-BR-3 cell lines. A competition study with non-radioactive GM-BDA yielded an IC50 value of 1.35 ± 0.14 nM, underscoring the probe's affinity for HSP90. In xenograft models of MDA-MB-231 breast cancer, [64Cu]Cu-DOTA-BDA-GM showcased targeted tumor localization, with significant radioactivity observed up to 18 h post-injection. Blocking studies using unlabeled GM-BDA and treatment with the anticancer drug Vorinostat (SAHA), which can affect the expression and activity of numerous proteins, such as HSPs, confirmed the specificity and sensitivity of the probe in cancer targeting. Additionally, PET/CT imaging in a lung metastasis mouse model revealed increased lung uptake of [64Cu]Cu-DOTA-BDA-GM in metastatic sites, significantly higher than in non-metastatic lungs, illustrating the probe's ability to detect metastatic breast cancer. In conclusion, [64Cu]Cu-DOTA-BDA-GM represents a sensitive and specific approach for identifying HSP90 expression in breast cancer and metastases, offering promising implications for clinical diagnosis and monitoring.

Effect of veno-arterial extracorporeal membrane oxygenation lower-extremity cannulation on intra-arterial flow characteristics, oxygen content, and thrombosis risk.

PURPOSE: This study aimed to investigate the effects of lower-extremity cannulation on the intra-arterial hemodynamic environment, oxygen content, blood damage, and thrombosis risk under different levels of veno-arterial (V-A) ECMO support. METHODS: Computational fluid dynamics methods were used to investigate the effects of different levels of ECMO support (ECMO flow ratios supplying oxygen-rich blood 100-40 %). Flow rates and oxygen content in each arterial branch were used to determine organ perfusion. A new thrombosis model considering platelet activation and deposition was proposed to determine the platelet activation and thrombosis risk at different levels of ECMO support. A red blood cell damage model was used to explore the risk of hemolysis. RESULTS: Our study found that partial recovery of cardiac function improved the intra-arterial hemodynamic environment, with reduced impingement of the intra-arterial flow field by high-velocity blood flow from the cannula, a flow rate per unit time into each arterial branch closer to physiological levels, and improved perfusion in the lower extremities. Partial recovery of cardiac function helps reduce intra-arterial high shear stress and residence time, thereby reducing blood damage. The overall level of hemolysis and platelet activation in the aorta decreased with the gradual recovery of cardiac contraction function. The areas at high risk of thrombosis under V-A ECMO femoral cannulation support were the aortic root and the area distal to the cannula, which moved to the descending aorta when cardiac function recovered to 40-60 %. However, with the recovery of cardiac contraction function, hypoxic blood pumped by the heart is insufficient in supplying oxygen to the front of the aortic arch, which may result in upper extremity hypoxia. CONCLUSION: We developed a thrombosis risk prediction model applicable to ECMO cannulation and validated the model accuracy using clinical data. Partial recovery of cardiac function contributed to an improvement in the aortic hemodynamic environment and a reduction in the risk of blood damage; however, there is a potential risk of insufficient perfusion of oxygen-rich blood to organs.