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Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

Neural Regeneration Research 2024年第3期19卷 529-535页

作者： Sandro Huenchuguala Juan Segura-Aguilar Escuela de Tecnología Médica Facultad de SaludUniversidad Santo TomásLos CarrerasOsornoChile molecular&clinical Pharmacology Instituto de Ciencias Biomedicas(ICBM)Faculty of medicineUniversity of ChileIndependenciaSantiagoChile

The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal *** preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical ***,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic *** lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big *** our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic *** exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic *** endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in t

关键词： 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 6-hydroxydopamine aminochrome dopaminergic neurons DT-diaphorase exogenous neurotoxins glutathione transferase M2-2

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Deep insight into the B-cell associated tertiary lymphoid structure and tumor immunotherapy

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cancer Biology & medicine 2024年第2期21卷 125-131页

作者： Jilong Yang Jin Xu Haotian Liu Wanyi Xiao Gengpu Zhang department of Bone and Soft Tissue Tumor Tianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Molecular Cancer EpidemiologyTianjin 300060China department of Anaesthesiology Tianjin University Tianjin HospitalTianjin 300211China

Bod et al.1 recently published a study in Nature that garnered attention to B cell-associated anti-tumor immunity and immunotherapy of melanoma and other *** a promising supplemental immunotherapy to mainstream method... 详细信息

关键词： immunotherapy immunity

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Reconstruction of Postinfarcted Cardiac Functions Through Injection of Tanshinone IIA@ Reactive Oxygen Species-Sensitive Microspheres Encapsulated in a Thermoreversible Hydrogel

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Energy & Environmental Materials 2024年第2期7卷 191-203页

作者： Ling Yu Yubin Liang Lei Gao Peipei Chen Zhiqiang Yu Minzhou Zhang Aleksander Hinek Shuai Mao Second clinical College Guangzhou University of Chinese Medicine department of Critical Care medicine Guangdong Provincial Hospital of Chinese Medicine Guangdong Provincial Branch of National clinical Research Centre for Chinese medicine Cardiology department of Radiation medicine and Applied Sciences University of California San Diego department of Laboratory medicine Dongguan Institute of Clinical Cancer Research Affiliated Dongguan Hospital Southern Medical University Translational medicine Hospital for Sick Children

Myocardial damage resulting from acute myocardial infarction often leads to progressive heart failure and sudden death, highlighting the urgent clinical need for effective therapies. Recently, tanshinone IIA has been identified as a promising therapeutic agent for myocardial infarction. However, efficient delivery remains a major issue that limits clinical translation. To address this problem, an injectable thermosensitive poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid-co-glycolic acid) gel(PLGA-PEG-PLGA) system encapsulating tanshinone IIA-loaded reactive oxygen species-sensitive microspheres(Gel-MS/tanshinone IIA) has been designed and synthesized in this study. The thermosensitive hydrogel exhibits good mechanical properties after reaching body temperature. Microspheres initially immobilized by the gel exhibit excellent reactive oxygen speciestriggered release properties in a high-reactive oxygen species environment after myocardial infarction onset. As a result, encapsulated tanshinone IIA is effectively released into the infarcted myocardium, where it exerts local antipyroptotic and anti-inflammatory effects. Importantly, the combined advantages of this technique contribute to the mitigation of left ventricular remodeling and the restoration of cardiac function following tanshinone ***, this novel, precision-guided intra-tissue therapeutic system allows for customized local release of tanshinone IIA, presenting a promising alternative treatment strategy aimed at inducing beneficial ventricular remodeling in the post-infarct heart.

关键词： myocardial infarction ROS-sensitive polymer tanshinone IIA thermoreversible hydrogel ventricular remodeling

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MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 594-604页

作者： Yanjin WANG Yifei CHEN Fuji YANG Xiaolong YU Ying CHU Jing ZHOU Yongmin YAN Jianbo XI department of Laboratory medicine Wujin Hospital Affiliated with Jiangsu UniversityJiangsu UniversityChangzhou 213017China department of Laboratory medicine School of MedicineJiangsu UniversityZhenjiang 212013China Changzhou Key Laboratory of molecular Diagnostics and Precision cancer medicine Wujin Clinical College of Xuzhou Medical UniversityChangzhou 213017China

Liver fibrosis is a significant health burden,marked by the consistent deposition of ***,the currently available treatment approaches for this condition are far from *** oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver *** stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver *** studies have found that MSC-sEV can be used for microRNA delivery into target cells or *** is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC ***,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver *** study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis *** results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in ***,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in ***-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse ***-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 *** conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.

关键词： Mesenchymal stem cell(MSC) Small extracellular vesicle(sEV) MicroRNA-4465(miR-4465) Hepatic stellate cell(HSC) Liver fibrosis

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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military Medical Research 2024年第1期11卷 34-49页

作者： Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor *** the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment *** evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully *** Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of *** investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo *** signaling pathway components were evaluated using multi-omics *** were performed to elucidate the regulation of lipid metabolic reprogramming of *** We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic ***,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain *** Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of ***2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

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PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma

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Genes & Diseases 2024年第4期11卷 340-352页

作者： Rui Liu Yi Liu Wenlu Zhang Guiji Zhang Zhirong Zhang Luyi Huang Ni Tang Kai Wang Key Laboratory of molecular Biology for Infectious Diseases(Ministry of Education) Institute for Viral HepatitisDepartment of Infectious DiseasesThe Second Affiliated HospitalChongqing Medical UniversityChongqing 400016China department of clinical Laboratory Sichuan Clinical Research Center for CancerSichuan Cancer Hospital&InstituteSichuan Cancer CenterAffiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduSichuan 610041China

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic *** carboxylase 1(PCK1),a gluconeogenic metabolic enzyme,is down-regulated in hepatocellular carcinoma and is closely related to poor *** onco-genesis and progression of tumors are closely related to cancer stem *** is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular ***,the results showed that PCK1 inhibited the self-renewal property of hepatoma cells,reduced the mRNA level of cancer stem cell markers,and inhibited ***,PCK1 increased the sensitivity of hepatocellular carci-noma cells to ***,we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear *** reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of ***,combined treatment with verteporfin and sorafenib may be a potential anti-tumor strat-egy in hepatocellular carcinoma.

关键词： cancer stem cells Chemoresistance Gluconeogenesis Hepatocellular carcinoma YAP

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The evolution of cancer genomic medicine in Japan and the role of the National cancer Center Japan

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cancer Biology & medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno department of Genetic medicine and Services National Cancer Center HospitalTokyo 104-0045Japan department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan department of Pathology and clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National cancer Center Research Institute Tokyo 104-0045Japan department of Laboratory medicine National Cancer Center HospitalTokyo 104-0045Japan department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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Weight change and all-cause and cause-specific mortality:A 25-year follow-up study

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Chinese Medical Journal 2024年第10期137卷 1169-1178页

作者： Huan Yang Jianbing Wang Xiaokun Wang Wanyi Sun Chenyunhao Tong Jinhu Fan Youlin Qiao Christian *** department of cancer Epidemiology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China department of Public Health Zhejiang University School of MedicineNational Clinical Research Center for Children’s HealthHangzhouZhejiang 310058China Metabolic Epidemiology Branch Division of Cancer Epidemiology and GeneticsNational Cancer InstituteRockvilleMD 20850USA

Background:Whether the dynamic weight change is an independent risk factor for mortality remains *** study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial(NIT)***:Body weight of 21,028 healthy residents of Linxian,Henan province,aged 40-69 years was measured two times from 1986 to *** events were prospectively collected up to *** maintenance group(weight changecancer(HR_(cancer)=1.12,95%CI:1.03-1.21,P=0.009),and heart disease(HR_(Heart diseases)=1.21,95%CI:1.11-1.31,Pcancer)=0.89,95%CI:0.79-0.99,P=0.033)lower risk of cancer mortality and 23%higher risk of stroke mortality(HR_(Stroke)=1.23,95%CI:1.12-1.34,Pcancer death(HR_(Overweight to normal)=1.20,95%CI:1.04-1.39;HR_(Becoming underweight)=1.44,95%CI:1.24-1.67),while stable overweight could increase the risk of total death(HR_(Stable overweight)=1.11,95%CI:1.05-1.17)and death from stroke(HR_(Stable overweight)=1.44,95%CI:1.33-1.56).Interaction effects were observed between age and weight change on cancer mortality,as well as between baseline BMI and weight change on all-cause,heart disease,and stroke mortality(all P_(

关键词： Weight change All-cause mortality cancer Stroke Heart diseases Body mass index

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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

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Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li department of medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&molecular Research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

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Machine learning applications in stroke medicine:advancements,challenges,and future prospectives

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Neural Regeneration Research 2024年第4期19卷 769-773页

作者： Mario Daidone Sergio Ferrantelli Antonino Tuttolomondo Internal medicine and Stroke Care Ward Department of Health PromotionMother and Child CareInternal Medicine and Medical SpecialtiesUniversity of Palermo molecular and clinical medicine PhD Program University of Palermo

Stroke is a leading cause of disability and mortality worldwide,necessitating the development of advanced technologies to improve its diagnosis,treatment,and patient *** recent years,machine learning techniques have emerged as promising tools in stroke medicine,enabling efficient analysis of large-scale datasets and facilitating personalized and precision medicine *** abstract provides a comprehensive overview of machine learning’s applications,challenges,and future directions in stroke *** introduced machine learning algorithms have been extensively employed in all the fields of stroke *** learning models have demonstrated remarkable accuracy in imaging analysis,diagnosing stroke subtypes,risk stratifications,guiding medical treatment,and predicting patient *** the tremendous potential of machine learning in stroke medicine,several challenges must be *** include the need for standardized and interoperable data collection,robust model validation and generalization,and the ethical considerations surrounding privacy and *** addition,integrating machine learning models into clinical workflows and establishing regulatory frameworks are critical for ensuring their widespread adoption and impact in routine stroke *** learning promises to revolutionize stroke medicine by enabling precise diagnosis,tailored treatment selection,and improved *** research and collaboration among clinicians,researchers,and technologists are essential for overcoming challenges and realizing the full potential of machine learning in stroke care,ultimately leading to enhanced patient outcomes and quality of *** review aims to summarize all the current implications of machine learning in stroke diagnosis,treatment,and prognostic *** the same time,another purpose of this paper is to explore all the future perspectives these techniques can provide in combating this disabling dis

关键词： cerebrovascular disease deep learning machine learning reinforcement learning stroke stroke therapy supervised learning unsupervised learning

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