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Upregulation of circ0000381 atienuates microglial/macrophage pyroptosis after spinal cord injury

Neural Regeneration Research 2024年第6期19卷 1360-1366页

作者： Yan Zhang Wenkai Zhang Tao Liu Ziqian Ma Wenxiu Zhang Yun Guan Xueming Chen Central Laboratory Beijing Luhe Hospital Capital Medical University Department of Orthopedics Beijing Luhe Hospital Capital Medical University Department of Emergency Medicine Aerospace Center Hospital Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Department of Neurological Surgery Johns Hopkins University School of Medicine

Neuroinflammation exacerbates secondary damage after spinal cord injury, while microglia/macrophage pyroptosis is important to neuroinflammation. Circular RNAs(circRNAs) play a role in the central nervous system. However, the functional role and mechanism of circRNAs in regulating microglia/macrophage pyroptosis after spinal cord injury are still poorly studied. In the present study, we detected microglia/macrophage pyroptosis in a female rat model of spinal cord injury, along with upregulated levels of circ0000381 in the spinal cord. Our further experimental results suggest that circ0000381 may function as a sponge to sequester endogenous microRNA423-3p(miR-423-3p), which can increase the expression of NOD-like receptor 3(NLRP3), a pyroptosis marker. Therefore, upregulation of circ0000381 may be a compensatory change after spinal cord injury to attenuate microglia/macrophage pyroptosis. Indeed, knockdown of circ0000381 expression exacerbated microglia/macrophage pyroptosis. Collectively, our findings provide novel evidence for the upregulation of circ0000381, which may serve as a neuroprotective mechanism to attenuate microglia/macrophage pyroptosis after spinal cord injury. Accordingly, circ0000381 may be a novel therapeutic target for the treatment of spinal cord injury.

关键词： circ0000381 inflammasome macrophage microglia miR-423-3p neuroinflammation neuroprotection NLRP3 pyroptosis RNA-Seq spinal cord injury

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Origins of perturbations in dayside equatorial ground magnetograms

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Earth and Planetary Physics 2024年第1期8卷 215-221页

作者： Syau-Yun W.Hsieh David G.Sibeck The johns hopkins University Applied Physics Laboratory LaurelMarylandUSA NASA Goddard Space Flight center GreenbeltMarylandUSA

To determine the cause(s)of perturbations seen in dayside equatorial ground magnetograms,we conducted a systematic survey of simultaneous ground-based and geosynchronous satellite-based observations during the 90-day period from December 1,2020 to February 28,2021.We examined Huancayo ground magnetometer observations from 14:00:00 to 20:00:00 UT each day,during which Huancayo passed through local noon.From those data we chose perturbation events selected on the basis of large(>20 nT)event amplitude and classified the selected events as responding primarily to solar wind pressure,or to variations in the north/south component of the interplanetary magnetic field(IMF Bz),or perhaps in part to both.The results show that an equivalent number of events were identified for each model during this 90-day period.Variations in the lagged solar wind dynamic pressure routinely correspond to nearly simultaneous sudden impulses recorded at both geosynchronous orbit and on the ground.Variations in IMF Bz produce erosion signatures at geosynchronous orbit and can correspond to ground events if lag times for reconnection to enhance convection in the magnetosphere are taken into account.

关键词： dayside magnetosphere dayside equatorial ionosphere geosynchronous magnetic field

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Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis

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Neural Regeneration Research 2024年第5期19卷 1105-1111页

作者： Tao Liu Ziqian Ma Liang Liu Yilun Pei Qichao Wu Songjie Xu Yadong Liu Nan Ding Yun Guan Yan Zhang Xueming Chen Department of Orthopedic Surgery Beijing Luhe HospitalCapital Medical UniversityBeijingChina Department of Orthopedic Surgery Beijing Chaoyang HospitalCapital Medical UniversityBeijingChina Department of Stomatology Beijing Luhe HospitalCapital Medical UniversityBeijingChina Department of Anesthesiology and Critical Care Medicine School of MedicineJohns Hopkins UniversityBaltimoreMDUSA Department of Neurological Surgery School of MedicineJohns Hopkins UniversityBaltimoreMDUSA

Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear.In the present study,we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells.We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury,decreased expression of the microglial pyroptosis markers NLRP3,GSDMD,caspase-1,and interleukin-1β,promoted axonal and myelin regeneration,and inhibited the formation of glial scars.In addition,in a lipopolysaccharide-induced BV2 microglia model,conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway.These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway,thereby promoting the recovery of neurological function after spinal cord injury.Therefore,conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.

关键词： BV2 conditioned medium dental pulp stem cells GSDMD microglia neuroinflammation NLRP3 pyroptosis spinal cord injury

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The impact of broad glutamine metabolism inhibition on the tumor microenvironment

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Genes & Diseases 2024年第3期11卷 2-4页

作者： Tianhe Li Yun-Ta Chuang Tian-Li Wang Departments of Pathology Oncologyand Gynecology and ObstetricsThe Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21231USA

Glutamine is an importantα-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides,proteins,and lipids.It also generates metabolites that fuel the tricarboxylic acid cycle and maintain intracellular redox balances.Malignant cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia,nutrient depletion.

关键词： metabolism tumor microenvironment

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A Simple Proof of ACC for Minimal Log Discrepancies for Surfaces

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Acta Mathematica Sinica,English Series 2024年第2期40卷 425-434页

作者： Jing Jun HAN Yu Jie LUO Shanghai center for Mathematical Sciences Fudan UniversityJiangwan CampusShanghai 200438P.R.China Department of Mathematics Johns Hopkins UniversityBaltimoreMD 21218USA

Following Shokurov's idea,we give a simple proof of the ACC conjecture for minimal log discrepancies for surfaces.

关键词： Ascending chain condition minimal log discrepancies minimal model program surface

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Drug repurposing for cancer therapy

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1981-2013页

作者： Ying Xia Ming Sun Hai Huang Wei-Lin Jin center for Clinical Laboratories The Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004PR China The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine Guiyang 550001PR China School of Clinical Laboratory Science Guizhou Medical UniversityGuiyang 550004PR China Division of Gastroenterology and Hepatology Department of Medicine andDepartment of OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21287USA Institute of Cancer Neuroscience Medical Frontier Innovation Research CenterThe First Hospital of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityLanzhou 730000PR China

Cancer,a complex and multifactorial disease,presents a significant challenge to global health.Despite significant advances in surgical,radiotherapeutic and immunological approaches,which have improved cancer treatment outcomes,drug therapy continues to serve as a key therapeutic strategy.However,the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects,and thus there remains a critical need to develop novel cancer therapeutics.One promising strategy that has received widespread attention in recent years is drug repurposing:the identification of new applications for existing,clinically approved drugs.Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective,proven to be safe,and can significantly expedite the drug development process due to their already established safety profiles.In light of this,the present review offers a comprehensive overview of the various methods employed in drug repurposing,specifically focusing on the repurposing of drugs to treat cancer.We describe the antitumor properties of candidate drugs,and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment.In addition,we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery.We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen.To conclude,we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

关键词： drugs integrating spite

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Acquiring Weak Annotations for Tumor Localization in Temporal and Volumetric Data

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Machine Intelligence Research 2024年第2期21卷 318-330页

作者： Yu-Cheng Chou Bowen Li Deng-Ping Fan Alan Yuille Zongwei Zhou Department of Computer Science Johns Hopkins UniversityBaltimore 21218USA Computer Vision Lab ETH ZurichZurich 8001Switzerland

Creating large-scale and well-annotated datasets to train AI algorithms is crucial for automated tumor detection and localization.However,with limited resources,it is challenging to determine the best type of annotations when annotating massive amounts of unlabeled data.To address this issue,we focus on polyps in colonoscopy videos and pancreatic tumors in abdominal CT scans;Both applications require significant effort and time for pixel-wise annotation due to the high dimensional nature of the data,involving either temporary or spatial dimensions.In this paper,we develop a new annotation strategy,termed Drag&Drop,which simplifies the annotation process to drag and drop.This annotation strategy is more efficient,particularly for temporal and volumetric imaging,than other types of weak annotations,such as per-pixel,bounding boxes,scribbles,ellipses and points.Furthermore,to exploit our Drag&Drop annotations,we develop a novel weakly supervised learning method based on the watershed algorithm.Experimental results show that our method achieves better detection and localization performance than alternative weak annotations and,more importantly,achieves similar performance to that trained on detailed per-pixel annotations.Interestingly,we find that,with limited resources,allocating weak annotations from a diverse patient population can foster models more robust to unseen images than allocating per-pixel annotations for a small set of images.In summary,this research proposes an efficient annotation strategy for tumor detection and localization that is less accurate than per-pixel annotations but useful for creating large-scale datasets for screening tumors in various medical modalities.

关键词： Weak annotation detection localization segmentation colonoscopy abdomen

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Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

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Chinese medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of Hepatobiliary-Pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney Kimmel Comprehensive Cancer center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic targets.Cancer-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and metabolism.Single-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been defined.However,the precise functions of these subtypes need to be studied and validated.Studies of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic targets.Some clinical trials,including phase III trials targeting CAFs,have been performed recently.However,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be performed.This review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving CAFs.Additionally,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： Cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

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Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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Neural Regeneration Research 2024年第5期19卷 1045-1055页

作者： Allison Loan Charvi Syal Margarita Lui Ling He Jing Wang Regenerative Medicine Program Ottawa Hospital Research InstituteOttawaONCanada Department of Biology Faculty of ScienceUniversity of OttawaOttawaONCanada Department of Pediatrics and Medicine Johns Hopkins Medical SchoolBaltimoreMDUSA Department of Cellular and Molecular Medicine Faculty of MedicineUniversity of OttawaOttawaONCanada University of Ottawa Brain and Mind Research Institute OttawaONCanada

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

关键词： Alzheimer’s disease Huntington’s disease metformin mitochondrial perturbation multiple sclerosis neural degenerative diseases Parkinson’s disease stroke targeted therapy

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Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1525-1541页

作者： Qi Shang Wandong Liu Faith Leslie Jiapei Yang Mingmei Guo Mingjiao Sun Guangji Zhang Qiang Zhang Feihu Wang School of Biomedical Engineering Shanghai Jiao Tong UniversityShanghai 200240China School of Basic medical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province Hangzhou 310053China Department of Chemical and Biomolecular Engineering Whiting School of Engineeringthe Johns Hopkins UniversityBaltimoreMD 21218USA Traditional Chinese Medicine“Preventing Disease”Wisdom Health Project Research center of Zhejiang Hangzhou 310053China Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.

关键词： Chinese herbal medicines Nano-formulation Activeingredients Drug delivery Cancer immunotherapy Innate immune system Adaptive immune system

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