Ferroptosis, which is caused by iron‐dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the ...regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis‐associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis‐based antitumor therapy.
This discovery suggests that CARM1‐mediated ACSL4 R339 methylation is a vital regulatory mechanism for ferroptosis resistance and tumor progression. Additionally, CARM1 may be highlighted as a candidate therapeutic target for improving the effects of ferroptosis‐based antitumor therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this paper, the details and design process of an optical system for space target detection cameras are introduced. The whole system is divided into three structures. The first structure is a ...short-focus visible light system for rough detection in a large field of view. The field of view is 2°, the effective focal length is 1,125 mm, and the F-number is 3.83. The second structure is a telephoto visible light system for precise detection in a small field of view. The field of view is 1°, the effective focal length is 2,300 mm, and the F-number is 7.67. The third structure is an infrared light detection system. The field of view is 2°, the effective focal length is 390 mm, and the F-number is 1.3. The visible long-focus narrow field of view and visible short-focus wide field of view are switched through a turning mirror. Design results show that the modulation transfer functions of the three structures of the system are close to the diffraction limit. It can further be seen that the short-focus wide-field-of-view distortion is controlled within 0.1%, the long-focus narrow-field-of-view distortion within 0.5%, and the infrared subsystem distortion within 0.2%. The imaging effect is good and the purpose of the design is achieved.
Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is ...the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.
Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.
The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A wave glider is a novel unmanned marine vehicle which can convert marine energy into kinetic energy. In practice, it is crucial for the wave glider system to deploy into the ocean environment ...efficiently and safely. Hence, the present work establishes the wave glider motion equations to analyze the deployment method. Firstly, the wave glider model is simplified in the vertical plane and the cable model is defined as mass nodes connected with a massless spring. Then, two typical deployment methods (Method 1 and Method 2) are proposed based on the multibody dynamic method, and the numerical simulation model is established to investigate the kinematic performance of two deployment methods. Lastly, the dynamic characteristic analysis is conducted to select the determined deployment method. We explain the practical advantages of Method 1, which would provide the reference for the deployment method selection.
Nutlin-3a is an MDM2 inhibitor that is under investigation in preclinical models for a variety of pediatric malignancies, including retinoblastoma, rhabdomyosarcoma, neuroblastoma, and leukemia. We ...used physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of nutlin-3a in the mouse. Plasma protein binding and blood partitioning were assessed by in vitro studies. After intravenous (10 and 20 mg/kg) and oral (50, 100, and 200 mg/kg) dosing, tissue concentrations of nutlin-3a were determined in plasma, liver, spleen, intestine, muscle, lung, adipose, bone marrow, adrenal gland, brain, retina, and vitreous fluid. The PBPK model was simultaneously fit to all pharmacokinetic data using NONMEM. Nutlin-3a exhibited nonlinear binding to murine plasma proteins, with the unbound fraction ranging from 0.7 to 11.8%. Nutlin-3a disposition was characterized by rapid absorption with peak plasma concentrations at approximately 2 h and biphasic elimination consistent with a saturable clearance process. The final PBPK model successfully described the plasma and tissue disposition of nutlin-3a. Simulations suggested high bioavailability, rapid attainment of steady state, and little accumulation when administered once or twice daily at dosages up to 400 mg/kg. The final model was used to perform simulations of unbound tissue concentrations to determine which dosing regimens are appropriate for preclinical models of several pediatric malignancies.
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