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Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

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Asian Journal of Pharmaceutical sciences 2024年第1期19卷 69-85页

作者： Noehyun Myung Hyun-Wook Kang Department of biomedical Engineering Ulsan National Institute of Science and Technology(UNIST)Ulju-gun 44919South Korea

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

关键词： Dose-dense chemotherapy Triple-negative breast cancer 3D printing Pulsatile release Local drug delivery systems

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Long-term in vivo chimeric cells tracking in non-human primate

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Protein & Cell 2024年第3期15卷 207-222页

作者： Junmo Wu Yu Kang Xiang Luo Shaoxing Dai Yuxi Shi Zhuoyao Li Zengli Tang Zhenzhen Chen Ran Zhu Pengpeng Yang Zifan Li Hong Wang Xinglong Chen Ziyi Zhao Weizhi ji Yuyu Niu State Key Laboratory of Primate biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China Yunnan Key Laboratory of Primate biomedical Research Kunming 650500China Faculty of Life science and Technology Kunming University of Science and TechnologyKunming 650500China

Non-human primates(NHPs)are increasingly used in preclinical trials to test the safety and efficacy of biotech-nology therapies.Nonetheless,given the ethical issues and costs associated with this model,it would be highly advantageous to use NHP cellular models in clinical studies.However,developing and maintaining the naive state of primate pluripotent stem cells(PSCs)remains difficult as does in vivo detection of PSCs,thus limiting biotech-nology application in the cynomolgus monkey.Here,we report a chemically defined,xeno-free culture system for culturing and deriving monkey PSCs in vitro.The cells display global gene expression and genome-wide hypometh-ylation patterns distinct from monkey-primed cells.We also found expression of signaling pathways components that may increase the potential for chimera formation.Crucially for biomedical applications,we were also able to integrate bioluminescent reporter genes into monkey PsCs and track them in chimeric embryos in vivo and in vitro.The engineered cells retained embryonic and extra-embryonic developmental potential.Meanwhile,we generated a chimeric monkey carrying bioluminescent cells,which were able to track chimeric cells for more than 2 years in living animals.Our study could have broad utility in primate stem cell engineering and in utilizing chimeric monkey models forclinical studies.

关键词： pluripotent stem cells bioluminescence imaging non-human primates

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ELK3-ID4 axis governs the metastatic features of triple negative breast cancer

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Oncology Research 2024年第1期32卷 127-138页

作者： JIN-HO CHOI JOO DONG PARK SEUNG HEE CHOI EUN-SU KO HYE JUNG JANG KYUNG-SOON PARK Department of biomedical science CHA UniversitySeongnamKorea

Purpose:Cancer cell metastasis is a multistep process,and the mechanism underlying extravasation remains unclear.ELK3 is a transcription factor that plays a crucial role in regulating various cellular processes,including cancer metastasis.Based on the finding that ELK3 promotes the metastasis of triple-negative breast cancer(TNBC),we investigated whether ELK3 regulates the extravasation of TNBC by forming the ELK3-ID4 axis.ID4 functions as a transcriptional regulator that interacts with other transcription factors,inhibiting their activity and subsequently influencing various biological processes associated with cell differentiation,survival,growth,and metastasis.Methods:We assessed the correlation between the expression of ELK3 and that of ID4 in TNBCs using bioinformatics analyses,QRT-PCR,western blot analysis,luciferase reporter assays,and chromatin immunoprecipitation.Migration,adhesion,invasion,and lung metastasis assays were employed to determine whether the ELK3-ID4 axis regulates the metastatic features of TNBC.Results:We found that ELK3 binds directly to a binding motif close to the ID4 promoter to repress promoter activity.The expression of E-cadherin in TNBC was regulated by the ELK3-ID4 axis.In vitro and in vivo analyses showed that inhibiting ID4 expression in ELK3-knockdown MDA-MB-231(ELK3KD)cells restored the ability to extravasate and metastasize.Conclusion:The results indicate that the ELK3 regulates ID4 promoter activity,and that the ELK3-ID4 axis regulates the metastatic characteristics of TNBC cells.Additionally,the data suggest that the ELK3-ID4 axis regulates metastasis of TNBCs by modulating expression of E-cadherin.

关键词： E-cadherin Extravasation Colonization

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Cell reprogramming therapy for Parkinson’s disease

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Neural Regeneration Research 2024年第11期19卷 2444-2455页

作者： Wenjing Dong Shuyi Liu Shangang Li Zhengbo Wang State Key Laboratory of Primate biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan ProvinceChina Yunnan Key Laboratory of Primate biomedical Research KunmingYunnan ProvinceChina

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

关键词： animal models astrocytes autologous cell reprogramming cell therapy direct lineage reprogramming dopaminergic neurons induced pluripotent stem cells non-human primates Parkinson’s disease

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Loss of SHROOM3 affects neuroepithelial cell shape through regulating cytoskeleton proteins in cynomolgus monkey organoids

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Zoological Research 2024年第2期45卷 233-241页

作者： Peng Li Ting Zhang Ruo Wu Jun-Yu Zhang Yan Zhuo Shan-Gang Li Jiao-Jian Wang Wen-Ting Guo Zheng-Bo Wang Yong-Chang Chen State Key Laboratory of Primate biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China Yunnan Key Laboratory of Primate biomedical Research KunmingYunnan 650500China

Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure.Although folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often attributable to genetic factors,remain unpreventable.The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation;at present,however,the underlying mechanism remains unclear.Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate.To determine the role of SHROOM3 in early developmental morphogenesis,we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase.Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei.These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins,namely fibrous actin(F-actin),myosin II,and phospho-myosin light chain(PMLC),to the apical side of the neuroepithelial cells.Notably,these defects were not rescued by folate supplementation.RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis.In summary,we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.

关键词： Neural tube defects SHROOM3 Neuroepithelial Organoids Cynomolgus monkey

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Biomimetic microchannel network with functional endothelium formed by sacrificial electrospun fibers inside 3D gelatin methacryloyl(GelMA)hydrogel models

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Journal of Zhejiang University-science A(Applied Physics & Engineering) 2024年第1期25卷 79-96页

作者： Haoyu SUN Haiyang MA Li WANG Yang LIU Tian HOU Wenjie TANG Qing YU Meiwen AN Meiling WEN institute of biomedical Engineering College of Biomedical EngineeringTaiyuan University of TechnologyTaiyuan030024China

Three-dimensional(3D)hydrogel models play a crucial role in tissue engineering for promoting tissue regeneration.A biomimetic microchannel network system in the 3D hydrogel model is necessary for optimal cellular function.This report describes the preparation of a biomimetic hydrogel scaffold with an internal microchannel network,using electrospinning techniques and the sacrificial template method for 3D cell culture.Microchannels and cavities were created within the gelatin methacryloyl(GelMA)hydrogel by sacrificing polyvinyl alcohol(PVA)electrospun fibers(>10µm),resulting in the creation of microvessel-like channels.Mechanical characterizations,swelling properties,and biodegradation analysis were conducted to investigate the feasibility of a biomimetic microchannel network hydrogel scaffold for 3D cell culture applications.Compared to pure GelMA hydrogel,the hydrogel with microchannels promoted cell proliferation,adhesion,and endothelial tube formation.Moreover,the results confirmed that the biomimetic microchannel network scaffold had a major impact on the distribution and arrangement of human umbilical vein endothelial cells(HUVECs)and can enable the formation of artificial microvasculature by the culture of HUVECs and cell media perfusion.

关键词： Biomimetic scaffold Photocrosslinking Microchannel network Tissue engineering Artificial microvascular

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Neurovascular unit on a chip: the relevance and maturity as an advanced in vitro model

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Neural Regeneration Research 2024年第6期19卷 1165-1166页

作者： Sujey Palma-Florez Anna Lagunas Mònica Mir Nanobioengineering Group Institute for Bioengineering of Catalonia (IBEC) Barcelona Institute of Science and Technology (BIST) Department of Electronics and biomedical Engineering University of Barcelona CIBER-BBN ISCIII

The brain is a high-energy demanding organ, consuming around 20% of the metabolic energy generated. To fulfill this demand, cerebral blood flow(CBF) supplies oxygen and glucose continuously through the intricate network of cerebral blood vessels. Although for many years brain activity and blood flow were conceived as independent processes, MRI-based functional brain imaging demonstrated that there is a coupling between them,

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Aberration correction for deformable-mirror-based remote focusing enables high-accuracy whole-cell super-resolution imaging

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Photonics Research 2024年第4期12卷 821-832页

作者： WEI SHI YINGCHUAN HE JIANLIN WANG LULU ZHOU JIANWEI CHEN LIWEI ZHOU ZEYU XI ZHEN WANG KE FANG YIMING LI Department of biomedical Engineering Southern University of Science and TechnologyShenzhen 518055China

Single-molecule localization microscopy(SMLM)enables three-dimensional(3D)investigation of nanoscale structures in biological samples,offering unique insights into their organization.However,traditional 3D super-resolution microscopy using high numerical aperture(NA)objectives is limited by imaging depth of field(DOF),restricting their practical application to relatively thin biological samples.Here,we developed a unified solution for thick sample super-resolution imaging using a deformable mirror(DM)which served for fast remote focusing,optimized point spread function(PSF)engineering,and accurate aberration correction.By effectively correcting the system aberrations introduced during remote focusing and sample aberrations at different imaging depths,we achieved high-accuracy,large DOF imaging(~8μm)of the whole-cell organelles[i.e.,nuclear pore complex(NPC),microtubules,and mitochondria]with a nearly uniform resolution of approximately 35 nm across the entire cellular volume.

关键词： enable mirror resolution

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Effect of Ga on the microstructure and properties of NiCoV alloy at different annealing temperatures

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Progress in Natural science:Materials International 2024年第2期34卷 408-419页

作者： Jin Li Peng Wang Lvxing Chen Meifeng He Jun Cheng School of Materials and Chemistry University of Shanghai for Science and Technology Northwest institute for Nonferrous Metal Research Shaanxi Key Laboratory of Biomedical Metal Materials

To obtain a high-entropy alloy characterized by high strength and plasticity,（NiCoV）100-xGaxx=0,5,7) was successfully prepared,cold-rolled,and heat-treated.The microstructure was analyzed to correlate Ga content with the performance of the system.The addition of Ga can produce alloying effects,including solid solution strengthening effect,second phase precipitation strengthening effect,and layer misalignment energy reduction effect.The experimental results show adding Ga elements can enrich Ni,Co,V,and Ga above the grain boundaries,causing the alloy to produce annealed twins inside.The alloy is strengthened mainly by precipitation,and the formation of the precipitation phase effectively enhances the strength of the alloy.The low stacking fault energy promotes the toughening of NiCoV but makes the plasticity of the alloy decrease.Still,the formation of annealed twins effectively increases the plasticity,which makes the alloy harder but does not reduce the plasticity too much.By comparing the experimental properties,（NiCoV）93Ga7showed the best mechanical properties at the annealing temperature of 900℃,yield strength,tensile strength and elongation of 906 MPa,1321 MPa and21.36 %,respectively.

关键词： Annealing treatment High entropy alloy Mechanical properties Precipitation strengthening Twin strengthening

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Multisensory Conflict Impairs Cortico-Muscular Network Connectivity and Postural Stability: Insights from Partial Directed Coherence Analysis

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Neuroscience Bulletin 2024年第1期40卷 79-89页

作者： Guozheng Wang Yi Yang Kangli Dong Anke Hua Jian Wang Jun Liu Key Laboratory for biomedical Engineering of Ministry of Education College of Biomedical Engineering&Instrument ScienceZhejiang UniversityHangzhou 310058China Taizhou Key Laboratory of Medical Devices and Advanced Materials Research Institute of Zhejiang University-TaizhouTaizhou 318000China Department of Sports science College of EducationZhejiang UniversityHangzhou 310058China Center for Psychological science Zhejiang UniversityHangzhou 310058China

Sensory conflict impacts postural control,yet its effect on cortico-muscular interaction remains underexplored.We aimed to investigate sensory conflict's influence on the cortico-muscular network and postural stability.We used a rotating platform and virtual reality to present subjects with congruent and incongruent sensory input,recorded EEG(electroencephalogram)and EMG(electromyogram)data,and constructed a directed connectivity network.The results suggest that,compared to sensory congruence,during sensory conflict:(1)connectivity among the sensorimotor,visual,and posterior parietal cortex generally decreases,(2)cortical control over the muscles is weakened,(3)feedback from muscles to the cortex is strengthened,and(4)the range of body sway increases and its complexity decreases.These results underline the intricate effects of sensory conflict on cortico-muscular networks.During the sensory conflict,the brain adaptively decreases the integration of conflicting information.Without this integrated information,cortical control over muscles may be lessened,whereas the muscle feedback may be enhanced in compensation.

关键词： Cortico-muscular interaction Postural control Virtual reality Electroencephalogram Electromyography Sensory integration

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