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JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

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Research on the pathophysiological mechanism of carotid artery dissection and its clinical translation is limited due to the lack of effective animal models to simulate the occurrence of this condition. Assuming that intimal injury is an important factor in the formation of carotid dissection, we established a novel method for inducing carotid dissection models by scraping the carotid intima using a fine needle. Scraping the carotid intima with fine needles can induce the rapid formation of carotid dissection. Magnetic resonance imaging and hematoxylin-eosin staining suggest the presence of false lumens and mural hematomas in the vessels. Our model-induction technique, inspired by iatrogenic catheter-induced artery dissections (carotid, coronary, aortic), significantly mimics the pathological process of clinical carotid dissection. The results suggest that mechanical injury may be a significant cause of carotid dissection and that intimal injury is a major factor in the formation of arterial dissections. This approach will provide assistance in the understanding of medically induced arterial dissection.

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G-protein-coupled receptor kinase 2 (GRK2) interacts with Gßγ and Gαq, subunits of G-protein alpha, to regulate cell signalling. The second messenger inositol trisphosphate, produced by activated Gαq, promotes calcium release from the endoplasmic reticulum (ER) and regulates maturation-promoting factor (MPF) activity. This study aimed to investigate the role of GRK2 in MPF activity during the meiotic maturation of porcine oocytes. A specific inhibitor of GRK2 (ßi) was used in this study. The present study showed that GRK2 inhibition increased the percentage of oocyte arrest at the metaphase I (MI) stage (control: 13.84 ± 0.95%; ßi: 31.30 ± 4.18%), which resulted in the reduction of the maturation rate (control: 80.36 ± 1.94%; ßi: 65.40 ± 1.14%). The level of phospho-GRK2 decreased in the treated group, suggesting that GRK2 activity was reduced upon GRK2 inhibition. Furthermore, the addition of ßi decreased Ca2+ release from the ER. The protein levels of cyclin B and cyclin-dependent kinase 1 were higher in the treatment group than those in the control group, indicating that GRK2 inhibition prevented a decrease in MPF activity. Collectively, GRK2 inhibition induced meiotic arrest at the MI stage in porcine oocytes by preventing a decrease in MPF activity, suggesting that GRK2 is essential for oocyte meiotic maturation in pigs.

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PURPOSE: To investigate the safety and effectiveness of radiotherapy for advanced upper tract urothelial carcinoma (UTUC) patients intolerant to chemotherapy. METHODS: Data for 21 patients with advanced UTUC intolerant to chemotherapy were retrospectively collected. All patients were treated with conventionally fractionated radiotherapy (50-70 Gy/20-33 f) or partial-SABR boost to the lesions (50-60 Gy/20-25 f with tumor center boosted with 6-8 Gy/f, 3-5 f) for bulky tumors. RESULTS: The median age was 75 years (range, 58-87 years). Primary tumor resection was performed for all patients and none underwent metastatic resection. Seventeen (81%) patients had oligometastasis (1-5 metastases) at diagnosis. Eighteen (85.7%) received irradiation to all tumor lesions. Lymph node metastasis was predominant in the whole group (17/21). Other lesions were distributed as local recurrence (7/21), bone metastases (2/21) and abdominal wall/muscle (2/21). The median follow-up time was 38.5 months (interquartile range, 15.2-48.7 months). Rate of local control (LC), progression-free survival (PFS) and overall survival (OS) of the whole group at 1 year were 90%, 46.6%, and 80.4%, respectively. At 3 years, LC, PFS and OS were 65.6%, 26.6%, and 40.9%, respectively. Fourteen patients developed acute mild gastrointestinal toxicity, generally of grade 1-2; 8 patients developed acute grade 1-2 hematological toxicity, consisting mainly of anemia and leukopenia. No grade 3 or higher acute or late toxicities were observed. CONCLUSION: For patients with advanced UTUC who are not able to tolerate chemotherapy, radiotherapy is a safe treatment and can achieve good local tumor control.

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Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti-fibrotic and anti-inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine-induced chronic tubulointerstitial nephropathy (TIN) and in idole-3-acetic acid (IAA)-stimulated NRK-52E cells. Acetate and n-butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF-ƙB) and its target gene products as well as activated antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA-stimulated NRK-52E cells. The inhibitory effect of GPA on AHR, NF-Ƙb, and Nrf2 signaling were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191 compared with untreated IAA-stimulated NRK-52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling.

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Organic fluorophores with tunable π-conjugated paths have attracted considerable attention owing to their diverse properties and promising applications. Herein, we present a tailored butterfly like molecule, 2,2'-(2,5-bis (2,2-diphenylvinyl)-1,4-phenylene)dinaphtha-lene (BDVPN), which exhibits diverse photophysical features in its two polymorphs. The BP phase crystal, with its "aligned wings" conformation, possesses emissive characteristics that are nearly identical to those in dilute solutions. In contrast, the BN phase crystal, which adopts an "orthogonal wings" conformation, exhibits an unusual hypsochromic-shifted emission compared to its dilute solution counterparts. This intriguing hypsochromic-shifted emission originates from the reduction in the effective conjugated length of the molecular skeleton. Notably, BN phase crystals also exhibit exceptional optical performance, featuring high-efficiency emission (76.6%), low-loss optical waveguides (0.571 dB mm-1), deep-blue amplified spontaneous emission (ASE) with a narrow full width at half maximum (FWHM: 6.4 nm), and a unique 200 nm bathochromic shift of piezochromic luminescence.

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OBJECTIVES: To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class Ⅲ to V. METHODS: A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class Ⅱ group (12 cases) and a class Ⅲ to Ⅴ group (18 cases). The risk factors for the occurrence of class Ⅲ to Ⅴ SLN were analyzed, and the prognostic characteristics were summarized. RESULTS: Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class Ⅱ and class Ⅲ to V groups (P>0.05). However, three patients in the class Ⅱ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class Ⅱ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class Ⅲ to V SLN in children (P<0.05). CONCLUSIONS: Class Ⅲ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class Ⅲ to V SLN in children.

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As emerging and re-emerging pathogens, filoviruses, especially Ebola virus (EBOV), pose a great threat to public health and require sustained attention and ongoing surveillance. More vaccines and antiviral drugs are imperative to be developed and stockpiled to respond to unpredictable outbreaks. Virus-like vesicles, generated by alphavirus replicons expressing homogeneous or heterogeneous glycoproteins (GPs), have demonstrated the capacity of self-propagation and shown great potential in vaccine development. Here, we describe a novel class of EBOV-like vesicles (eVLVs) incorporating both EBOV GP and VP40. The eVLVs exhibited similar antigenicity as EBOV. In murine models, eVLVs were highly attenuated and elicited robust GP-specific antibodies with neutralizing activities. Importantly, a single dose of eVLVs conferred complete protection in a surrogate EBOV lethal mouse model. Furthermore, our VLVs strategy was also successfully applied to Marburg virus (MARV), the representative member of the genus Marburgvirus. Taken together, our findings indicate the feasibility of an alphavirus-derived VLVs strategy in combating infection of filoviruses represented by EBOV and MARV, which provides further evidence of the potential of this platform for universal live-attenuated vaccine development.

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Objective: This study investigated the clinical effects and applicability of minimally invasive impacted teeth extraction using digital robots. Methods: A marker was bonded to the non-surgical area before surgery. A Cone-Beam Computed Tomography (CBCT) scan was obtained and uploaded to the robot software to determine the drilling position of the ring drill. During the surgery, the robot arm automatically navigated to a predetermined position, and the ring drill removed part of the bone tissue and exposed and extracted the impacted teeth. Finally, the surgeon tightly sutured the wounds to the surgical area. Results: Three minimally invasive extractions of impacted teeth with robotic assistance were performed without complications. The surgical area showed good healing during the one-month follow-up examination. Conclusions: Digital robot-assisted minimally invasive extraction of impacted teeth is a highly feasible clinical procedure as it minimises trauma to the surgical area and protects the surrounding blood vessels and nerve bundles, making it a safe and valuable technique with significant potential for clinical application.

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Purpose: This study aims to explore the effectiveness of enhancing individual spatial cognitive abilities in alleviating the negative symptoms of visually induced motion sickness (VIMS). Additionally, it seeks to develop innovative intervention methods to improve spatial cognition and identify new treatment approaches for VIMS. Methods: The study investigated the impact of innovative interventions on spatial cognitive abilities and their modulation of VIMS susceptibility. A total of 43 participants were recruited (23 in the experimental group and 20 in the control group). The experimental group underwent six sessions of spatial cognitive ability training, while the control group engaged in activities unrelated to spatial cognition. Results: The analysis revealed that the spatial cognitive ability scores of the experimental group significantly improved after the intervention. Furthermore, the experimental group exhibited significant differences in nausea, oculomotor, disorientation, and total SSQ scores before and after the intervention, indicating that the intervention effectively mitigated VIMS symptoms. Conclusion: This study developed a virtual reality training method that effectively enhances individual spatial cognitive abilities and significantly alleviates VIMS symptoms, providing a novel and effective approach for VIMS intervention and treatment.

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BACKGROUND: Carnosine, a natural bioactive dipeptide derived from meat muscle, possesses strong antioxidant properties. Dexamethasone, widely employed for treating various inflammatory diseases, raises concerns regarding its detrimental effects on bone health. This study aimed to investigate the protective effects of carnosine against dexamethasone-induced oxidative stress and bone impairment, along with its underlying mechanisms, utilizing chick embryos and a zebrafish model in vivo, as well as MC3T3-E1 cells in vitro. RESULTS: Our findings revealed that carnosine effectively mitigated bone injury in dexamethasone-exposed chick embryos, accompanied by reduced oxidative stress. Further investigation demonstrated that carnosine alleviated impaired osteoblastic differentiation in MC3T3-E1 cells and zebrafish by suppressing the excessive production of reactive oxygen species (ROS) and enhancing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, mechanistic studies elucidated that carnosine promoted the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby facilitating the transcription of its downstream antioxidant response elements, including heme oxyense-1 (HO-1), glutamate cysteine ligase modifier (GCLM), and glutamate cysteine ligase catalytic (GCLC) to counteract dexamethasone-induced oxidative stress. CONCLUSION: Overall, this study underscores the potential therapeutic efficacy of carnosine in mitigating oxidative stress and bone damage induced by dexamethasone exposure, shedding light on its underlying mechanism of action by activating the NRF2 signaling pathway. © 2024 Society of Chemical Industry.

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OBJECTIVE: This paper aims to enhance exoskeleton compliance during locomotion assistance by reducing misalignment and to improve energy efficiency by overcoming the limitations posed by the bulky structure of powered rigid exoskeletons. METHODS: A novel compliant knee exoskeleton, featuring a parallel elastic self-alignment mechanism, has been developed and structurally optimized. The exoskeleton uses adaptive oscillators to determine the wearer's gait phase and provides real-time assistance to the knee joint. RESULTS: Bench tests demonstrate that the parallel elastic mechanism significantly reduces the driving torque of the knee exoskeleton. Performance evaluations reveal that, compared to a commercial orthosis, the root-mean-square of knee angle error, joint misalignment, and unexpected interaction forces are reduced by 16.5 ± 11.3%, 23.3 ± 4.9%, and 17.7 ± 1.3%, respectively. Gait intervention experiments show reductions in average and maximum muscle activity of the knee joint by 7.6 ± 4.9% and 23.2 ± 5.7%, respectively. Additionally, the exoskeleton decreases negative work performed by the knee joint and the total lower limb by 22.7% and 8.6%, respectively. CONCLUSION: The parallel elastic self-alignment mechanism effectively mitigates joint misalignment, while the parallel springs offer partial gravity compensation, thereby enhancing both the energy efficiency and locomotion assistance of the exoskeleton. SIGNIFICANCE: The parallel elastic self-alignment mechanism effectively addresses both misalignment and energy efficiency challenges in powered exoskeletons, providing valuable insights for future design improvements.

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VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.

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Two-dimensional valleys and magnetism are rising areas with intriguing properties and practical uses in advanced information technology. By coupling valleys to collinear magnetism, valley degeneracy is lifted in a large number of magnetic valley materials to exploit the valley degree of freedom. Beyond collinear magnetism, new coupling modes between valley and magnetism are few but highly desirable. By tight-binding calculations of a breathing Kagome lattice, we demonstrate a tunable valley structure and valley-contrasting physical properties in noncollinear antiferromagnets. Distinct from collinear magnetism, noncollinear antiferromagnetic order enables valley splittings even without spin-orbit coupling. Both the canting and azimuthal angles of magnetic moments can be used as experimentally accessible knobs to tune valley splittings. Our first-principles calculations of the Fe3C6O6-silicene-Fe3C6O6 heterostructure also exhibit tunable valley splittings in noncollinear antiferromagnetism, agreeing with our tight-binding results. Our work paves avenues for designing novel magnetic valley materials and energy-efficient valleytronic devices based on noncollinear magnetism.

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INTRODUCTION: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive. METHODS: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain. RESULTS: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury. CONCLUSION: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better-transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids.

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Three neutral Pt(II) complexes with diphenylamino-modified 2-phenylpyridine derivatives as cyclometalating ligands and acetylacetone as the ancillary ligand exhibit aggregation-induced phosphorescent emission (AIPE) properties in THF/H2O. The crystal structures of the complexes highlight the contributions of non-covalent Pt···Pt interactions and hydrogen bonds to the AIPE properties. These AIPE-active Pt(II) complexes 1-3 have been successfully applied to detect picric acid (PA) in aqueous media, affording the lowest limit of detection at 70 nM. Furthermore, three Pt(II) complexes are able to detect PA in common water samples. The quenching of luminescence in the detection can be attributed to photo-induced electron transfer.

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Methionine adenosyltransferase 2A (MAT2A) is an essential enzyme in the methionine cycle that generates S-adenosylmethionine (SAM) by reacting with methionine and ATP. SAM acts as a methyl donors for histone and DNA methylation, which plays key roles in zygotic genome activation (ZGA). However, the effects of MAT2A on porcine ZGA remain unclear. To investigate the function of MAT2A and its underlying mechanism in porcine ZGA, MAT2A was knocked down by double-stranded RNA injection at the 1-cell stage. MAT2A is highly expressed at every stage of porcine embryo development. The percentages of four-cell-stage embryos and blastocysts were lower in the MAT2A-knockdown (KD) group than in the control group. Notably, depletion of MAT2A decreased the levels of H3K4me2, H3K9me2/3, and H3K27me3 at the four-cell stage, whereas MAT2A KD reduced the transcriptional activity of ZGA genes. MAT2A KD decreased embryonic ectoderm development (EED) and enhancer of zeste homolog 2 (EZH2) expression. Exogenous SAM supplementation rescued histone methylation levels and developmental arrest induced by MAT2A KD. Additionally, MAT2A KD significantly increased DNA damage and apoptosis. In conclusion, MAT2A is involved in regulating transcriptional activity and is essential for regulating histone methylation during porcine ZGA.

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PURPOSE: Investigating the effects of unequal sub-arc personalized collimator angle selection on the quality of Volumetric Modulated Arc Therapy (VMAT) plans for treating multiple brain metastases. METHODS: This study included 21 patients, each with 2-4 target volumes of multiple brain metastases. Two stereotactic radiotherapy (SRT) approaches were utilized: sub-arc collimator VMAT (SAC-VMAT) and fixed collimator VMAT (FC-VMAT). In the SAC-VMAT group, multi-leaf collimators (MLC) shaped the target area, dividing the full arc into four unequal sub-arcs under the beam's eye view (BEV). Each sub-arc had an appropriate collimator angle selected to mitigate 'island blocking problems'. Conversely, the FC-VMAT group used a fixed collimator angle of 15° or 345°. A comparative analysis of the dosimetric parameters of the target volumes and normal tissues, along with the monitor units (MU), was conducted between the two groups. RESULTS: The mean dose and dose-volume to normal brain tissue (2-26 Gy, with a step of 2 Gy) were significantly lower in the SAC-VMAT group (P < 0.01). There was no statistical difference between the two groups in dose to the target volumes, conformity index (CI), homogeneity index (HI), and other normal tissues (P > 0.05). Compared with the FA-VMAT group, the SAC-VMAT group significantly reduced the gradient index (GI) (4.5 ± 0.59 vs 5.2 ± 0.75, P < 0.001) and MU (1774.33 ± 181.77 vs 2001.0 ± 344.86, P < 0.001). Notably, with an increase in the number of PTV, the SAC-VMAT group demonstrated more significant improvements in the dose-volume of normal brain tissue, GI, and MU. CONCLUSIONS: In this study, personalized selection of the unequal sub-arc collimator angle ensured the prescribed dose to the PTV, CI, and HI, while significantly reducing the GI, MU, and the dose to normal brain tissue in the VMAT plan for multi-target brain metastases in the cohort of cases with 2-4 target volumes. Particularly as the number of targets increase, the advantages of this method become more pronounced.

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Flavopiridol (FP) is a plant-derived flavonoidis and used to treat cancers, fungal infections and inflammation-related diseases. However, it is not clear whether it has side effects on the female reproductive system. In this study, we aimed to investigate the toxic effects and potential underlying mechanisms of FP on oocyte maturation and cumulus cell expansion in mice. Cumulus-oocyte complexes (COCs) were cultured in vitro with FP of gradient concentration (50-1000nM), according to the plasma concentration of FP in the clinical trial. The maturation rate and cumulus expansion index of oocytes were counted and studied by immunofluorescence staining, qRT-PCR, oocyte chromosome preparation and so on. The results showed that the FP-exposed COCs inhibited the oocyte maturation and cumulus cell expansion, leading to cell apoptosis in a dose dependent way. Oocytes exposed to 500nM FP showed abnormalities in the spindle structure and chromosome arrangement, ultimately leading to the oocyte maturation arrest and aneuploidy. This may be due to the excessive oxidative stress caused by mitochondrial membrane potential damage and mislocalization. Therefore, when FP is used for cancer treatment, its side effects on the female reproductive system should be seriously considered.