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5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

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Oncology Research 2024年第6期32卷 1047-1061页

作者： KIMBERLY FENECH ISAAC MICALLEF BYRON BARON Centre for Molecular medicine and Biobanking University of MaltaMsidaMSD 2080Malta Department of Tumor Genetics and Biology Graduate School of Medical SciencesFaculty of Life SciencesKumamoto UniversityKumamoto860-8556Japan

Background:Colorectal cancer(CRC)is one of the most frequently diagnosed *** many cases,the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil(5-FU).The epithelial-to-mesenchymal transition(EMT)and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many *** study looked into the effect of 5-FU dose escalation on EMT and protein methylation in *** and Methods:HCT-116,Caco-2,and DLD-1 CRC cell lines were exposed to dose escalation treatment of *** motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion *** was followed by aWestern blot which analyzed the protein expressions of the epithelial marker E-cadherin,mesenchymal marker vimentin,and the EMT transcription factor(EMTTF),the snail family transcriptional repressor 1(Snail)in the parental and desensitized *** blotting was also conducted to study the protein expressions of the protein methyltransferases(PMTs),Euchromatic histone lysine methyltransferase 2(EHMT2/G9A),protein arginine methyltransferase(PRMT5),and SET domain containing 7/9(SETD7/9)along with the global lysine and arginine methylation ***:The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of *** 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental *** was reflected in the observed reduction in E-cadherin,vimentin,and Snail in the desensitized cell ***,the protein expressions of EHMT2/G9A,PRMT5,and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU ***:This study showed that continuous,dose-escalation treatment of 5-FU in CRC cells generated 5-FU

关键词： Chemoresistance Epithelial-to-mesenchymal transition Protein methylation Protein methyltransferases

Intranasal administration of stem cell-derived exosomes for central nervous system diseases

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Neural Regeneration Research 2024年第6期19卷 1249-1255页

作者： Shuho Gotoh Masahito Kawabori Miki Fujimura Department of Neurosurgery Hokkaido University Graduate School of MedicineHokkaidoJapan

Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular *** nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive *** findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system *** exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic ***,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug ***,researchers have turned their attention to exosomes as a novel therapeutic ***,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical *** overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous *** exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain ***,exosomes,owing to their small size,can readily access the nerve pathways using this *** a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased *** this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system ***,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

关键词： central nervous system disease exosome extracellular vesicle intranasal administration stem cell

Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models

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Neural Regeneration Research 2024年第9期19卷 1954-1960页

作者： Kinya Matsuo Hideaki Nshihara Yamaguchi university graduate school of medicine YamaguchiJapan Department of Neurotherapeutics Yamaguchi UniversityUbeJapan

The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous ***-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s ***,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal ***,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective *** elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional ***,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been *** in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain *** this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell ***,we discuss the potential future directions for blood-brain barrier research.

关键词： Alzheimer’s disease blood-brain barrier human induced pluripotent stem cells

Caspase-11 mediated inflammasome activation in macrophages by systemic infection of *** exacerbates arthritis

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International Journal of Oral Science 2024年第3期16卷 499-514页

作者： Tokuju Okano Hiroshi Ashida Noriko Komatsu Masayuki Tsukasaki Tamako Iida Marie Iwasawa Yuto Takahashi Yasuo Takeuchi Takanori Iwata Miwa Sasai Masahiro Yamamoto Hiroshi Takayanagi Toshihiko Suzuki Department of Bacterial Pathogenesis Infection and Host ResponseGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoTokyoJapan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoTokyoJapan Department of Lifetime Oral Health Care Science Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Periodontology Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Immunoparasitology Research Institute for Microbial DiseasesOsaka UniversityOsakaJapan

Clinical studies have shown that Aggregatibacter actinomycetemcomitans(***)is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis(RA).However,the mechanism is poorly ***,we show that systemic infection with *** triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis(CAIA)model following IL-1βsecretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in *** administration of polymyxin B(PMB),chloroquine,and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice,suggesting that the recognition of lipopolysaccharide(LPS)in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in *** data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with *** work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with ***.

关键词： CD11b inflam infection

Z-shaped incision without epithelial resection in pterygium surgery

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International Journal of Ophthalmology(English edition) 2024年第7期17卷 1262-1266页

作者： Satoru Kase Shinki Chin Susumu Ishida Department of Ophthalmology Faculty of Medicine and Graduate School of MedicineHokkaido UniversitySapporo 060-8638Japan

AIM:To introduce a novel surgical technique using a Z-shaped incision without epithelial resection in ophthalmic ***:This was a prospective *** pterygium surgery,all proliferative tissues were separated from the cornea and conjunctiva without resection of the *** unaffected conjunctiva was incised in a *** upper(or lower)conjunctival flap was sutured to the lower(or upper)normal conjunctiva on the limbal sclera,while the proliferative tissue was sutured to the upper conjunctiva(or lower)near the ***:Ten patients with pterygia were eligible for this *** patients with primary pterygia and 2 with recurrent pterygia were *** age of patients at surgery ranged from 47 to 90y(average:71.9y).Five patients each showed right and left-sided *** postoperative follow-up periods were from 8 to 78mo(average:25.0mo).The surgery was successfully conducted and wounds were favorably reconstructed in all *** proliferative tissues sutured to the normal conjunctiva showed palor and attenuated neovessles,and never showed re-growth after *** patients did not show *** pterygium was noted in 1 patient,but additional treatments were not ***:The procedure involves the reconstruction of pterygial tissue and normal conjunctiva using a Z-shaped *** scleral limbal wound can be covered with nonaffected conjunctiva without any excision of conjunctival epithelia in patients with primary or recurrent pterygia.

关键词： pterygium surgery Z-shape non-resection

Epigenetic memory of drug exposure history controls neural stem cell quiescence in the adult brain

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Neural Regeneration Research 2024年第4期19卷 711-712页

作者： Masakazu Iwamoto Taito Matsuda Department of Stem Cell Biology and medicine Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

Neural stem cells(NSCs)are the source of all neurons and glial cells(astrocytes and oligodendrocytes)in the central nervous *** adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in the hippocampus and ventricular subventricular zone lining the lateral ventricle(Olpe and Jessberger,2022).Adult NSCs in rodents are preserved throughout life and continuously produce new neurons that integrate into the pre-existing neuronal network.

关键词： neural integrate continuously

Dynamic Treatment Strategy of Chinese medicine for Metastatic Colorectal Cancer Based on Machine Learning Algorithm

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Chinese Journal of Integrative medicine 2024年第11期30卷 993-1000页

作者： XU Yu-ying LI Qiu-yan YI Dan-hui CHEN Yue ZHAI Jia-wei ZHANG Tong SUN Ling-yun YANG Yu-fei Department of Oncology Xiyuan Hospital China Academy of Chinese Medical Sciences school of Statistics Renmin University of China graduate school Beijing University of Chinese Medicine

Objective: To establish the dynamic treatment strategy of Chinese medicine(CM) for metastatic colorectal cancer(m CRC) by machine learning algorithm, in order to provide a reference for the selection of CM treatment strategies for m CRC. Methods: From the outpatient cases of m CRC in the Department of Oncology at Xiyuan Hospital, China Academy of Chinese Medical Sciences, 197 cases that met the inclusion criteria were screened. According to different CM intervention strategies, the patients were divided into 3 groups: CM treatment alone, equal emphasis on Chinese and Western medicine treatment(CM combined with local treatment of tumors, oral chemotherapy, or targeted drugs), and CM assisted Western medicine treatment(CM combined with intravenous regimen of Western medicine). The survival time of patients undergoing CM intervention was taken as the final evaluation index. Factors affecting the choice of CM intervention scheme were screened as decision variables. The dynamic CM intervention and treatment strategy for m CRC was explored based on the cost-sensitive classification learning algorithm for survival(CSCLSurv). Patients' survival was estimated using the Kaplan-Meier method, and the survival time of patients who received the model-recommended treatment plan were compared with those who received actual treatment plan. Results: Using the survival time of patients undergoing CM intervention as the evaluation index, a dynamic CM intervention therapy strategy for m CRC was established based on *** CM intervention strategies for m CRC can be selected according to dynamic decision variables, such as gender, age, Eastern Cooperative Oncology Group score, tumor site, metastatic site, genotyping, and the stage of Western medicine treatment at the patient's first visit. The median survival time of patients who received the modelrecommended treatment plan was 35 months, while those who receive the actual treatment plan was 26.0 months(P=0.06). Conclusions:

关键词： Chinese medicine cost sensitive classification learning for survival dynamic treatment strategy metastatic colorectal cancer

Recent trends in bone metastasis treatments:A historical comparison using the new Katagiri score system

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World Journal of Clinical Cases 2024年第15期12卷 2499-2505页

作者： Kenji Matsuda Kazuhiro Shimazu Hanae Shinozaki Koji Fukuda Taichi Yoshida Daiki Taguchi Kyoko Nomura Hiroyuki Shibata Department of Clinical Oncology Akita University Graduate School of MedicineAkita 010-8543Japan Department of Environmental Health Science and Public Health Akita University Graduate School of MedicineAkita 010-8543Japan Department of Comprehensive Cancer Control Akita University Graduate School of MedicineAkita 010-8543Japan

BACKGROUND Bone metastasis has various negative *** of daily living(ADL)and quality of life(QOL)can be significantly decreased,survival may be impacted,and medical expenses may *** is estimated that at least 5%cancer patients might be suffering from bone *** 2016,we published the Comprehensive Guidelines for the Diagnosis and Treatment of Bone *** then,the therapeutic outcomes for patients have gradually *** life expectancy is a major determinant of surgical intervention,the strategy should be modified if the prolongation of survival is to be *** To monitor how bone metastasis treatment has changed before and after launch of our guidelines for bone *** For advanced cancer patients with bone metastasis who visited the Department of Clinical Oncology at Akita university hospital between 2012 and 2023,parameters including the site and number of bone metastases,laboratory data,and survival time,were extracted from electronic medical records and the Katagiri score was *** association with survival was determined for each *** Data from 136 patients were *** 1-year survival rate for the poor prognosis group with a higher Katagiri score was 20.0%in this study,which was 6%and an apparent improvement from 2014 when the scoring system was *** factors significantly affecting survival included five or more bone metastases than less(P=0.0080),and treatment with chemotherapy(P<0.001),bone modifying agents(P=0.0175)and immune checkpoint inhibitors(P=0.0128).In recent years,advances in various treatment methods have extended the survival period for patients with advanced *** is necessary not only to simply extend survival time,but also to maintain ADL and improve *** Various therapeutic interventions including surgical approach for bone metastasis,which is a disorder of locomotor organs,are increasingly *** and scoring system for p

关键词： Bone metastasis New Katagiri scoring system Prognosis Immune check point inhibitors Survival

Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance

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Cellular & Molecular Immunology 2024年第4期21卷 393-408页

作者： Sujin Lee Yeunjung Ko Hyun Woo Lee Won Joon Oh Hun Gi Hong Dinuka Ariyaratne Se Jin Im Tae Jin Kim Department of Immunology Graduate School of Basic Medical ScienceSungkyunkwan University School of MedicineSuwon16419Republic of Korea Department of Immunology and Molecular medicine Faculty of Medical SciencesUniversity of Sri JayewardenepuraNugegodaSri Lanka Present address:Immunology and Microbiology graduate Program Baylor College of MedicineHoustonTX77030USA

Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous ***,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression ***80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B ***,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after *** of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine ***80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant ***80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B *** transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B *** summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.

关键词： Marginal Zone B Cell CD80 Autoreactivity Radioresistance