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Recirculating IL-1R2^(+) Tregs fine-tune intrathymic Treg development under inflammatory conditions

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Cellular & molecular Immunology 2021年第1期18卷 182-193页

作者： Eirini Nikolouli Yassin Elfaki Susanne Herppich Carsten Schelmbauer michael Delacher christine Falk Ilgiz A.mufazalov Ari Waisman markus Feuerer Jochen Huehn Department of Experimental Immunology Helmholtz Centre for Infection ResearchBraunschweigGermany Institute for molecular medicine University Medical Center of the Johannes Gutenberg-University MainzMainzGermany Regensburg Center for Interventional Immunology(RCI) Chair for ImmunologyUniversity Regensburg and University Hospital RegensburgRegensburgGermany Institute of Transplant Immunology Integrated Research and Treatment Center TransplantationIFB-TxHannover Medical SchoolHannoverGermany Hannover medical School HannoverGermany

The vast majority of Foxp3^(+)regulatory T cells(Tregs)are generated in the thymus,and several factors,such as cytokines and unique thymic antigen-presenting cells,are known to contribute to the development of these thymus-derived Tregs(tTregs).Here,we report the existence of a specific subset of Foxp3^(+)Tregs within the thymus that is characterized by the expression of IL-1R2,which is a decoy receptor for the inflammatory cytokine *** flow cytometric analysis of the thymocytes from Foxp3^(hCD2)xRAG1^(GFP) reporter mice revealed that the IL-1R2^(+)Tregs are mainly RAG1^(GFP-)and CCR6^(+)CCR7^(-),demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated *** the spleen,the majority of IL-1R2^(+)Tregs express neuropilin-1(Nrp-1)and Helios,suggesting a thymic origin for these ***,among all tissues studied,the highest frequency of IL-1R2^(+)Tregs was observed in the thymus,indicating preferential recruitment of this Treg subset by the *** fetal thymic organ cultures(FTOCs),we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development resulting in a decreased frequency of CD25^(+)Foxp3^(+)tTregs and an accumulation of CD25^(+)Foxp3^(-)Treg ***,the addition of IL-1R2^(+)Tregs,but not IL-1R2^(+)Tregs,to reaggregated thymic organ cultures(RTOCs)abrogated the IL-1β-mediated blockade,demonstrating that these recirculating IL-1R2^(+)Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.

关键词： Thymus Treg development Inflammation IL-1 system

Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

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Cancer Biology & medicine 2014年第4期11卷 237-246页

作者： Teresa Kim Rodabe N.Amaria christine Spencer Alexandre Reuben Zachary A.Cooper Jennifer A.Wargo Department of Surgery Massachusetts General Hospital Harvard medical School Department of melanoma medical Oncology University of Texas M.D.Anderson Cancer Center Department of Genomic medicine University of Texas M.D.Anderson Cancer Center Department of Surgical Oncology University of Texas M.D.Anderson Cancer Center

melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and mEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

关键词： melanoma checkpoint blockade BRAF inhibition immunotherapy

Toxicokinetic behavior assessment prediction of the ADmEProperties of alkylated naphthalenes by consideration of relevant physicochemical and dystemic toxicity data:Proof of concept

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Toxicokinetic behavior assessment prediction of the ADMEProp...

QT hysteresis in long-QT syndrome children with exercise testing

中国毒理学会第六届全国毒理学大会

作者： ming H KUNG christine m PALERmO Lawrence K LOW Exxonmobil Biomedical Sciences IncAnnandaleNJ

In some cases,it may be possible to predict the toxicokinetic behavior(ADmE) of a substance by considering its physicochemical properties as well as relevant toxicity data,such as data from a series of structurally related chemical *** is the approach supported by the European Union’ s REACH *** present case study aims to validate the toxicokinetic behavior assessment approach via comparison ofthe predicted ADmE properties of a substance to theexperimentally-determined ADmE properties fromrobust toxicokinetic(TK) studies with the radiolabeled *** case study was conducted with an alkylated naphthalene(AN) compound,AN-600,where600 denotes a molecular weight(mW) of 600 g·*** onits physicochemical properties,including molecular weight,water solubility and octanol/water partition coefficient(LogKow),AN-600 is predicted to have inherently low systemic *** was consistent with existing results of severaltoxicity studies in which there was no evidence of systemic absorption or *** was also predicted that among AN structural analogs differing in alkyl chain length and molecular weight,there would be an inverse relationship between molecular weight and bioavailability,consistent with pharmacologic *** inverse relationship prediction was supported byTK data from AN analogs,specifically AN-212(mW =212) and AN-379(mW=379) which had 85%and 10%oral bioavailability,***,there were observedtrends of decreasing systemic absorption in repeat - dose dermal studiesof AN-600 analogs with increasing molecular weight and there was no evidence of absorption found in a dermal study with AN- 600 ***,available basic TK data for analogs suggested that any absorbed material would be metabolized by side chain oxidation of the alkyl group,producing sulfate and glucuronide metabolites which would be ultimately excreted in the *** total,the above evidence led to a prediction that ve

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Chinese medical Journal 2007年第3期120卷 179-182页

作者： GAO Dong-sheng FANG Wei-yi christine Chiu-man Joel Kirsh Gil Gross Robert m. Hamilton Department of Cardiology Shanghai Chest Hospital Shanghai200030 China Department of Cardiology Hospital for Sick Children Universityof Toronto Ontario M5G 1X8 Canada

Background Congenital long QT syndrome （LQTS） is an inherited ion channel disorder resulting in abnormal cardiac repolarization that can cause syncope and sudden death associated with a prolonged rate-corrected QT interval and polymorphic ventricular tachycardia. Several studies in adults showed that LQTS patients have altered QT adaptation to heart rate changes compared with normal subjects which forming a ＂hysteresis loop＂ in the QT-circle length plot. This study was to observe the QT interval changing during exercise testing in children long QT syndrome （LQTS） patients, explore the new diagnosis methods of LQTS. methods The subjects were divided into 3 groups according to 1993 LQTS diagnostic criteria. Group 1： LQTS group （n=17） who scored 〉 or = 4 points indicating definite LQTS. Group 2： middle group （n=16）, patients who have prolonged QT interval but scored 1.5 to 3.5. Group 3： Normal control group （n=18）. The average age of all study population is （12.3±5.8） years. No case had beta-adrenergic antagonists administration before exercise testing. All subjects were underwent tread mill exercise testing and electrocardiograph in whole exercise testing and recovery were recorded. QT and heart rate changing during whole exercise testing period were recorded. /kQT, the QT interval at 1, 2, 4, 6 minutes into recovery subtract from the QT interval at a similar heart rate during exercise, were calculated. Results In all three groups, QT intervals were shortening with the increasing of heart rate, but QTc had no significant change. ΔQT at 1 minute （（45±11） ms）, 2 minutes （（37±15） ms）, 4 minutes （（23±12） ms） into recovery in LQTS group were significantly greater than that of the other two groups （P〈0.05, P〈0.01, P〈0.01, respectively）. There was no ΔQT significant difference between middle group and normal control group at recovery time. During the recovery phase in LQTS group, the QT interval remained shortened despite a decelerating heart rate, forming a hysteresis ＂lo

关键词： long QT syndrome QT hysteresis exercise testing children

Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model

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World Journal of Gastroenterology 2005年第44期11卷 6910-6919页

作者： Florian Graepler marie-Luise Lemken Wolfgang A Wybranietz Ulrike Schmidt Irina Smirnow christine D GroB martin Spiegel Andrea Schenk Schenk Hansj(o|¨)rg Graf Ulrike A Lauer Reinhard Vonthein michael Gregor Sorin Armeanu michael Bitzer Ulrich m.Lauer Department of Internal medicine Ⅰ Section of Experimental Radiology Department of medical Biometry

AIm： To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model. mETHODS： To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine （5-FC）, we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase （YCD） and the yeast uracil phosphoribosyltransferase （YUPRT） gene. RESULTS： In vitro stably transduced morris rat hepatoma cells （mH） expressing the bifunctional SuperCD suicide gene （mH SuperCD） showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with mH cells stably expressing YCD solely （mH YCD） or the cytosine deaminase gene of bacterial origin （mH BCD）, respectively. In vivo, mH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions （P〈0.01） under both high dose as well as low dose systemic 5-FC application, whereas mH tumors without transgene expression （mH naive） showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness （SuperCD〉〉 YCD〉〉BCD〉〉〉negative control） was defined as a result of a direct in vivo comparison of all three suicide genes. CONCLUSION： Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

关键词： YCD/YUPRT fusion Cytosine deaminase GDEPT Suicide gene therapy Hepatoma therapy

Pyridine Nucleotide Cycling and Control of Intracellular Redox State in Relation to Poly （ADP-Ribose） Polymerase Activity and Nuclear Localization of Glutathione during Exponential Growth of Arabidopsis Cells in Culture

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molecular Plant 2009年第3期2卷 442-456页

作者： Till K. Pellny Vittoria Locato Pedro Diaz Vivancos Jelena markovic Laura De Gara Federico V. Pallardo christine H. Foyer Plant Sciences Rothamsted Research Harpenden Hefts AL5 2 JQ UK CIR UniversitA Campus Bio-medico V. A. Del Portillo 21 00128 Roma Italy School of Agriculture Food and Rural Development Newcastle University Newcastle upon Tyne NE1 7RU UK Depto. de Fisiologia Av. Blasco Ibanez 15 46010 Valencia Spain Dipartimento di Biologia e Patologia Vegetale M E. Orabona 4 70125 Bari Italy

Pyridine nucleotides, ascorbate and glutathione are major redox metabolites in plant cells, with specific roles in cellular redox homeostasis and the regulation of the cell cycle. However, the regulation of these metabolite pools during exponential growth and their precise functions in the cell cycle remain to be characterized. The present analysis of the abundance of ascorbate, glutathione, and pyridine nucleotides during exponential growth of Arabidopsis cells in culture provides evidence for the differential regulation of each of these redox pools. Ascorbate was most abundant early in the growth cycle, but glutathione was low at this point. The cellular ascorbate to dehydroascorbate and reduced glutathione （GSH） to glutathione disulphide ratios were high and constant but the pyridine nucleotide pools were largely oxidized over the period of exponential growth and only became more reduced once growth had ceased. The glutathione pool increased in parallel with poly （ADP-ribose） polymerase （PARP） activities and with increases in the abundance of PARP1 and PARP2 mRNAs at a time of high cell cycle activity as indicated by transcriptome information. marked changes in the intracellular partitioning of GSH between the cytoplasm and nucleus were observed. Extension of the exponential growth phase by dilution or changing the media led to increases in the glutathione and nicotinamide adenine dinucleotide, oxidized form （NAD）-plus-nicotinamide adenine dinucleotide, reduced form （NADH） pools and to higher NAD/NADH ratios but the nicotinamide adenine dinucleotide phosphate, oxidized form （NADP）-plus-nicotinamide adenine dinucleotide phosphate, reduced form （NADPH） pool sizes, and NAPD/NADPH ratios were much less affected. The ascorbate, glutathione, and pyridine nucleotide pools and PARP activity decreased before the exponential growth phase ended. We conclude that there are marked changes in intracellular redox state during the growth cycle but that redox homeostasis is maint

关键词： glutathione ascorbate Redox control cell cycle cell signaling cell redox state.

Colorectal cancer risk following appendectomy:a pooled analysis of three large prospective cohort studies

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Cancer Communications 2022年第5期42卷 486-489页

作者： Joseph A.Rothwell Nagisa mori Fanny Artaud Agnès Fournier marco Conte marie-christine Boutron-Ruault Simon S.m.Chan marc J.Gunter Neil murphy Gianluca Severi UniversitéParis-Saclay UVSQInsermGustave RoussyExposome and Heredity teamCentre for Epidemiology and Population Health(CESP U1018)Villejuif 94800France Nutrition and metabolism Branch International Agency for Research on Cancer(IARC)150 Cours Albert ThomasLyon 69008France Department of Gastroenterology Norfolk and Norwich University Hospital NHS TrustNorwich NR47UYUnited Kingdom Department of medicine Bob Champion Research and Education BuildingNorwich Medical SchoolUniversity of East AngliaNorwich NR47UQUnited Kingdom Department of Statistics Computer ScienceApplications“G.Parenti”University of FlorenceFlorence 50134Italy

Dear Editor,Appendectomy is usually performed to treat acute appendicitis although it may also be conducted in the absence of appendicitis when patients suffer from chronic abdominal *** is also known to mitigate the risk of ulcerative colitis[1],a risk factor for colorectal *** impact of appendectomy on colorectal cancer risk,particularly in the long term,is *** procedurewas initially hypothesized to increase colorectal cancer risk due to decreased immunocompetency.

关键词： cancer colorectal acute

A direct real-time polymerase chain reaction assay for rapid high-throughput detection of highly pathogenic North American porcine reproductive and respiratory syndrome virus in China without RNA purification

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Journal of Animal Science and Biotechnology 2015年第1期6卷 22-28页

作者： Kang Kang Keli Yang Jiasheng Zhong Yongxiang Tian Limin Zhang Jianxin Zhai Li Zhang Changxu Song christine Yuan Gou Jun Luo Deming Gou College of Animal Science and Technology Northwest A&F University College of Life Sciences Shenzhen Key Laboratory of Microbial Genetic EngineeringShenzhen University Hubei Key Laboratory of Animal Embryo and molecular Breeding Institute of Animal Husbandry and VeterinaryHubei Academy of Agricultural Sciences Shenzhen Ao Dong Inspection and Testing Technology Co .Ltd Veterinary medicine Institute Guangdong Academy of Agricultural Sciences Northwestern University

Background： Porcine reproductive and respiratory syndrome virus （PRRSV）, and particularly its highly pathogenic genotype （HP-PRRSV）, have caused massive economic losses to the global swine industry. Results： To rapidly identify HP-PRRSV, we developed a direct reaL-time reverse transcription polymerase chain reaction method （dRT-PCR） that could detect the virus from serum specimen without the need of RNA purification Our dRT-PCR assay can be completed in 1.5 h from when a sample is received to obtaining a result. Additionally, the sensitivity of dRT-PCR matched that of conventional reverse transcription PCR （cRT-PCR） that used purified RNA The lowest detection limit of HP-PRRSV was 6.3 TCIDs0 using dRT-PCR. We applied dRT-PCR assay to 144 field samples and the results showed strong consistency with those obtained by cRT-PCR. moreover, the dRT-PCR method was able to tolerate 5-20% （v/v） serum. Conclusions： Our dRT-PCR assay allows for easier, faster, more cost-effective and higher throughput detection of HP-PRRSV compared with cRT-PCR methods. To the best of our knowledge, this is the first report to describe a real-time RT-PCR assay capable of detecting PRRSV in crude serum samples without the requirement for purifying RNA. We believe our approach has a great potential for application to other RNA viruses.

关键词： Highly pathogenic Porcine reproductive and respiratory syndrome virus Real-time RT-PCR

The Secrets in the Steam

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Journal of Health Science 2018年第3期6卷 178-182页

作者： Jennifer DeSilva christine Filippone Lisa m. martinez mary Ann Wells TammyLee Ranieri The Department of Epidemiology and Infection Prevention Community Medical Center Toms River 08755 USA

Introduction： There are several components in motion before steam reaches its destination. Each element plays a significant role in generating adequate steam for terminal sterilization of critical devices. The knowledge and awareness of factors that contribute to wet packs will assist in maximizing steam quality. Steam sterilization of critical devices such as surgical instruments in the acute care setting is fundamentally necessary to prevent infection. Sterile packaging that is wet after removal from the autoclave is considered contaminated. This wet pack presents a significant infection risk and indicates a defect in the sterilization process. The identification of wet packs prompted the exploration of the sterilization process. In reviewing the evolution of steam production, our investigation began in the boiler room. The assessments of the boiler operations, steam quality, and loading technique of the autoclaves were examined as possible contributing factors in the propagation of wet packs. methods： The investigation was performed in a 592-bed non-teaching acute care facility in New Jersey. methods to ensure the integrity of steam included; a cut point of 〈 3,500 ppm TDSs （total dissolved solids）, （daily） calibration of the TDS analyzer to ensure accurate TDS measurement, increase in autoclave drying times, reduction of the weight density of surgical trays from 25 lbs. to 20 lbs., and revision of sterilization loading practices. modifications were implemented from June 2015 to December 2015. Results： No wet packs were identified from January through may 2016. In June 2016, 2 wet packs were detected, and upon further analysis there was an increase in the water level of the boiler drum. After this special cause variation, no wet packs have been identified. Conclusion： The monitoring and documentation of boiler room parameters and CSP （central sterile processing） practice modifications may have impacted the reduction of wet pack.

关键词： Wet pack wet steam steam sterilization boiler operations.