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CD4^(+)T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors

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Cellular & Molecular Immunology 2024年第4期21卷 374-392页

作者： Xin Lei Daniël C.de Groot Marij J.P.Welters Tom de Wit Ellen Schrama Hans van Eenennaam Saskia J.Santegoets Timo Oosenbrug Annemarthe van der Veen Joris L.Vos Charlotte L.Zuur Noel F.C.C.de Miranda Heinz Jacobs Sjoerd H.van der Burg Jannie Borst Yanling Xiao Department of Immunology Leiden University Medical CenterLeidenThe Netherlands Oncode Institute Leiden University Medical CenterLeidenThe Netherlands Department of Tumor Biology and Immunology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of Medical Oncology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands IMMIOS B.V. OssThe Netherlands Division of Medical Oncology The Netherlands Cancer InstituteAmsterdamThe Netherlands Department of Otorhinolaryngology leiden university Medical Center LeidenThe Netherlands Department of Pathology Leiden University Medical CenterLeidenThe Netherlands

CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.

关键词： CD4^(+)T-cell help cDC1 licensing IFN-I signaling CD40 costimulation (cross-)presentation CTL priming Tumor control

Learning to select the recombination operator for derivative-free optimization

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Science China Mathematics 2024年第6期67卷 1457-1480页

作者： Haotian Zhang Jianyong Sun Thomas Back Zongben Xu School of Mathematics and Statistics Xi’an Jiaotong UniversityXi’an710049China leiden Institute of Advanced Computer Science Leiden UniversityLeiden2333 CANetherlands

Extensive studies on selecting recombination operators adaptively,namely,adaptive operator selection(AOS),during the search process of an evolutionary algorithm(EA),have shown that AOS is promising for improving EA's performance.A variety of heuristic mechanisms for AOS have been proposed in recent decades,which usually contain two main components:the feature extraction and the policy setting.The feature extraction refers to as extracting relevant features from the information collected during the search process.The policy setting means to set a strategy(or policy)on how to select an operator from a pool of operators based on the extracted feature.Both components are designed by hand in existing studies,which may not be efficient for adapting optimization problems.In this paper,a generalized framework is proposed for learning the components of AOS for one of the main streams of EAs,namely,differential evolution(DE).In the framework,the feature extraction is parameterized as a deep neural network(DNN),while a Dirichlet distribution is considered to be the policy.A reinforcement learning method,named policy gradient,is used to train the DNN.As case studies,the proposed framework is applied to two DEs including the classic DE and a recently-proposed DE,which result in two new algorithms named PG-DE and PG-MPEDE,respectively.Experiments on the Congress of Evolutionary Computation(CEC)2018 test suite show that the proposed new algorithms perform significantly better than their counterparts.Finally,we prove theoretically that the considered classic methods are the special cases of the proposed framework.

关键词： evolutionary algorithm differential evolution adaptive operator selection reinforcement learning deep learning

Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy

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CCS Chemistry 2024年第3期6卷 783-797页

作者： Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo Ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet Institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate School(SIGS)Tsinghua UniversityShenzhen 518055 leiden Institute of Chemistry Leiden University2333 CC Leiden Department of Chemistry Simon Fraser UniversityBurnabyBritish Columbia V5A 1S6 Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig38106 Braunschweig Department of Chemistry Johns Hopkins UniversityBaltimoreMaryland 21218 Division of Drug Discovery&Safety Leiden Academic Centre for Drug ResearchLeiden University2333 CC Leiden

Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer cells.However,in this model,the role of the ligand(s)coordinated to gold is often overlooked.In this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl ligand.The formation of a free Au(Ⅰ)center is responsible for the expected TrxR inhibition.Additionally,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium channel.Moreover,these ligands ended up in the lysosomes,resulting in significant lysosome damage.Altogether,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关键词： anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging prodrug

Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 308-325页

作者： Adilson Fonseca Teixeira Yanhong Wang Josephine Iaria Peter ten Dijke Hong-Jian Zhu Department of Surgery(The Royal Melbourne Hospital) The University of MelbourneParkvilleVICAustralia Huagene Institute Kecheng Science and Technology ParkPukou DistrictNanjingJiangsuChina Department of Cell and Chemical Biology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands

Metastasis is the leading cause of cancer-related deaths.Transforming growth factor beta(TGF-β)signaling drives metastasis and is strongly enhanced during cancer progression.Yet,the use of on-target TGF-βsignaling inhibitors in the treatment of cancer patients remains unsuccessful,highlighting a gap in the understanding of TGF-βbiology that limits the establishment of efficient anti-metastatic therapies.Here,we show that TGF-βsignaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle(sEV)secretion.Demonstrating sEV’s unique role,TGF-βsignaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β.Further,genetic disruption of sEV secretion in highlymetastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-βsignaling to nearly-normal levels.Otherwise,TGF-βsignaling activity in non-invasive breast cancer cells is inherently low,but can be amplified by sEVs,enabling invasion and metastasis of poorly-metastatic breast cancer cells.Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers,treatment with dimethyl amiloride(DMA)decreases sEV secretion,TGF-βsignaling activity,and breast cancer progression in vivo.Targeting both the sEV trafficking and TGF-βsignaling by combining DMA and SB431542 at suboptimal doses potentiated this effect,normalizing the TGF-βsignaling in primary tumors to potently reduce circulating tumor cells,metastasis,and tumor self-seeding.Collectively,this study establishes sEVs as critical elements in TGF-βbiology,demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-βsignaling levels in breast cancer cells.

关键词： metastasis doses invasion

Exploring the effects of taurolidine on tumor weight and microvessel density in a murine model of osteosarcoma

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Oncology Research 2024年第7期32卷 1163-1172页

作者： LISANNE K.A.NEIJENHUIS LEUTA L.NAUMANN SONIA A.M.FERKEL SAMUEL J.S.RUBIN STEPHAN ROGALLA Division of Gastroenterology and Hepatology Department of MedicineSchool of MedicineStanford UniversityStanford94305USA Department of Surgery Leiden University Medical CenterLeiden2333 ZAThe Netherlands Centre for Human Drug Research Leiden2333 CLThe Netherlands Department of General VisceralVascular and Thoracic SurgeryCharite University Medicine BerlinBerlin10117Germany

Background:Osteosarcoma is the most common malignant primary bone tumor.The prognosis for patients with disseminated disease remains very poor despite recent advancements in chemotherapy.Moreover,current treatment regimens bear a signiﬁcant risk of serious side effects.Thus,there is an unmet clinical need for effective therapies with improved safety proﬁles.Taurolidine is an antibacterial agent that has been shown to induce cell death in different types of cancer cell lines.Methods:In this study,we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma.K7M2 murine osteosarcoma cells were injected,both intramuscular and intraperitoneal,into 60 BALB/c mice on day zero.Animals were then randomized to receive treatment with taurolidine 2%(800 mg/kg),taurolidine 1%(400 mg/kg),or NaCl 0.9%control for seven days by intravenous or intraperitoneal administration.Results:After 35 days,mice were euthanized,and the tumors were harvested for analysis.Eighteen mice were excluded from the analysis due to complications.Body weight was signiﬁcantly lower in the 2%taurolidine intraperitoneal treatment group from day 9 to 21,consistent with elevated mortality in this group.Intraperitoneal tumor weight was signiﬁcantly lower in the 1%(p=0.003)and 2%(p=0.006)intraperitoneal taurolidine treatment groups compared to the control.No antineoplastic effects were observed on intramuscular tumors or for intravenous administration of taurolidine.There were no signiﬁcant differences in microvessel density or mitotic rate between treatment groups.Reduced body weight and elevated mortality in the 2%taurolidine intraperitoneal group suggest that the lower 1%dose is preferable.Conclusions:In conclusion,there is no evidence of antiangiogenic activity,and the antitumor effects of taurolidine on osteosarcoma observed in this study are limited.Moreover,its toxic proﬁle grants further evaluation.Given these observations,further research is necessary to reﬁne the use of taurolidine in osteosarcoma tre

关键词： Osteosarcoma Taurolidine Cancer treatment Chemotherapy Murine models

Assignment of the non-exchangeable proton resonances and conformational analysis of oligonucleotide DNA d(TTGGGGTT)by twodimensional nuclear magnetic resonance methods

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Chinese Journal of Chemistry 1990年第3期8卷 246-250页

作者： DONG,Yan-Hong TANG,Wen-Xia DAI,An-Bang Coordination Chemistry Institute,Nanjing university,Nanjing 210008WU,Jia-Zhen Beijing Biophysics Institute,Academia Sinica,Beijing 100080van BOOM,J.H. REEDIJK,J. STRUIK,A.F. Department of Chemistry,Gorlaeus Laboratories,leiden university,leiden,The Netherlands Coordination Chemistry Institute Nanjing University Nanjing 210008 Beijing Biophysics Institute Academia Sinica Beijing 100080 Department of Chemistry Gorlaeus Laboratories Leiden University Leiden The Netherlands

Two-dimensional NMR study on the single-stranded octadeoxynucleotide,d(TT- GGGGTT)is presented.Assignments of the base protons,the H1′,H2′ and H2″ protons were made by two-dimensional Nuclear Overhauser Enhancement Spectroscopy(NOESY)and two-dimensional homonuclear J-correlated Spectroscopy(COSY).The result indicates that the overall structure of the single-stranded d(TTGGGGTT)is a right-handed B-type helix.

关键词： Assignment of the non-exchangeable proton resonances and conformational analysis of oligonucleotide DNA d DNA

The Impact of Health Information Technology on Hospital Performance: A Systematic Integrative Literature Review

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Health 2024年第4期16卷 257-279页

作者： Alisa Westerhof Cokky Hilhorst Willem Jan Bos Accounting Auditing & Control Nyenrode Business University Breukelen Netherlands St. Antonius Ziekenhuis Utrecht Netherlands Department of Internal Medicine Nephrology Leiden University Medical Center Leiden Netherlands

Objective: To review, categorise, and synthesise findings from literature on health information technology (HIT) functionalities, HIT use, and the impact of HIT on hospital performance. Materials and Methods: We conducted a systematic integrative literature review based on a compre-hensive database search. To organise, categorise and synthesise the ex-isting literature, we adopted the affordance actualization theory. To align the literature with our research framework, we used four categories: 1) the functionalities of HIT and how these functionalities are measured;2) use and immediate outcomes of HIT functionalities;3) different perfor-mance indicators and how HIT functionalities affect them;and 4) what hospital characteristics influence the outcome of hospital performance. Results: Fifty-two studies were included. We identified four types of HIT. Only ten studies (19.2%) define the use of HIT by explicitly meas-uring the use rate of HIT. We identified five dimensions of hospital per-formance indicators. Every dimension showed mixed results;however, in general, HIT has a positive impact on mortality and patient readmis-sions. We found several hospital characteristics that may affect the rela-tionship between HIT and hospital-level outcomes. Discussion: Further efforts should focus on embedded research on HIT functionalities, use and effects of HIT implementations with more performance indicators and adjusted for hospital characteristics. Conclusion: The proposed framework could help hospitals and researchers make decisions regard-ing the functionalities, use and effects of HIT implementation in hospi-tals. Given our research outcomes, we suggest future research opportuni-ties to improve understanding of how HIT affects hospital performance. .

关键词： Health Information Technology HIT Functionalities Hospital Performance Indicators

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德国西宁根与中国灵井的骨器比较（英文）

人类学学报 2024年第2期43卷 214-232页

作者：王华李占扬 Thijs van KOLFSCHOTEN 山东大学环境与社会考古国际合作联合实验室山东大学考古学院 School of Archaeology Leiden University

相似性在人类体质、文化和技术等方面的演化过程中扮演着非常重要的角色。本文涉及到的两个遗址，位于德国的旧石器时代早期遗址西宁根13地点Ⅱ-4层和位于中国北方地区的旧石器时代中期灵井遗址10-11层，出土的考古遗存具有极大的相似... 详细信息

相似性在人类体质、文化和技术等方面的演化过程中扮演着非常重要的角色。本文涉及到的两个遗址，位于德国的旧石器时代早期遗址西宁根13地点Ⅱ-4层和位于中国北方地区的旧石器时代中期灵井遗址10-11层，出土的考古遗存具有极大的相似性。两个遗址保存状况都非常好，且均出土有大量的石器和动物化石。最为引人注意的是，两个遗址出土的动物遗存特点以及骨器相关的遗存也表现出多个方面的相似性。经鉴定，两个遗址均出土有多个种属的食肉动物、一种象，两种犀牛属动物、两种马科动物，多种鹿类以及牛科动物。两个遗址均出土有修整石器所用的骨质软锤，以及利用食草动物的掌跖骨制作的用于砸骨吸髓的骨锤。这些锤子的远端具有特定的破裂形态。考虑到两个遗址之间的距离以及年代差异，这些相似性非常值得关注，但我们不认为两个遗址的相似性代表的是文化上的联系。相反，我们认为这种相似性反映的是人类在相似的环境中采取了相似的行为模式，同时相似的埋藏条件也起到一定的作用。

关键词：旧石器时代露天遗址骨器中国欧洲

Terminology for a FAIR Framework for the Virus Outbreak Data Network-Africa

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Data Intelligence 2022年第4期4卷 698-723,1050页

作者： Ruduan Plug Yan Liang Aliya Aktau Mariam Basajja Francisca Oladipo Mirjam van Reisen leiden university 2331 GL Leidenthe Netherlands Kampala International university 260101 KampalaUganda leiden university Medical Centre(LUMC) Leiden University1310 Leidenthe Netherlands

The field of health data management poses unique challenges in relation to data ownership, the privacy of data subjects, and the reusability of data. The FAIR Guidelines have been developed to address these challenges. The Virus Outbreak Data Network(VODAN) architecture builds on these principles, using the European Union’s General Data Protection Regulation(GDPR) framework to ensure compliance with local data regulations, while using information knowledge management concepts to further improve data provenance and interoperability. In this article we provide an overview of the terminology used in the field of FAIR data management, with a specific focus on FAIR compliant health information management, as implemented in the VODAN architecture.

关键词： Data management Distributed data Federated data Data governance FAIR Guidelines FAIR Data and Services FAIR Data Point FAIR framework