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Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

Genes & Diseases 2024年第3期11卷 338-350页

作者： Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng State Key Laboratory of Molecular oncology and department of Radiation oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China department of General Surgery Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China department of Dermatology University of California San DiegoSan DiegoCA 92093USA department of oncology Mayo ClinicRochesterMN 55905USA

The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor *** is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy *** studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic *** this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)*** found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM *** regulation of AMPK requires the Hippo kinases but not LKB1/*** kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM ***,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival *** activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC ***,these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

关键词： AMPKactivity Cellularmetabolic switch ECM stiffness Hippokinase signaling Pancreaticductal adenocarcinoma

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Designing macrophage membrane-engineered ruthenium/selenium nanoparticles to block bone metastasis of breast cancer

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Nano Research 2024年第8期17卷 7504-7512页

作者： Meijin Yang Zhiying Tang Xiaoying Li Yanzi Yu Lizhen He Tianfeng Chen College of Chemistry and Materials Science Department of Oncology of The First Affiliated HospitalJinan UniversityGuangzhou 510632China

Bone metastasis along with osteolysis is a common complication of advanced breast cancer,which directly destroys bone function and becomes one of the major causes of cancer-related *** is crucial to develop a new strategy to achieve effective cancer therapy and inhibition of osteolytic bone *** ruthenium(Ru)complexes exhibit therapeutic potential in cancer ***,the clinical applications of Ru complexes were limited by poor bioavailability,lacking targeting,nonspecific ***,in this study,engineering of cell membrane biomimetic modification was used to construct a highly biocompatible nanoplatform with carrying Ru metal complex of RuPOP and Se nanoparticles(SeNPs).Strikingly,the obtained RPSR nanoparticles can efficiently inhibit the proliferation,invasion and migration of breast cancer cells(MDA-MB-231 cells)in *** importantly,RPSR nanoparticles can induce cycle arrest,apoptosis by generating excessive intracellular(reactive oxygen species,ROS)to disrupt the normal redox balance and induce DNA damage in tumor ***,RPSR nanoparticles can also reshape bone microenvironment by regulating selenoproteins to inhibit osteoclasts and avoid osteolytic bone metastasis induced by tumor *** together,this study not only provides an effective cell membrane biomimetic strategy to enhance the shortcomings of metal complexes,but also demonstrates potential clinical significance for the combined treatment of anti-cancer and bone metastasis inhibition.

关键词： cell membrane nanoparticles biomimetic modification ruthenium complexes selenium nanoparticles tumor bone metastasis

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Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

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Biomedical and Environmental Sciences 2024年第5期37卷 457-470页

作者： KONG Zi Qing LIU Li Qun HUANG De Qin WANG Yu Tong LI Jing Jie ZHANG Zheng WANG Xi Xi LIU Chuan Ling ZHANG Ya Di SHAO Jia Kang ZHU Yi Min CHEN Yi Meng LIU Mei ZHAO Wei Hong Medical School of Chinese PLA Beijing 100853China department of Medical oncology the First Medical CenterGeneral Hospital of the Chinese People’s Liberation ArmyBeijing 100853China Nankai University School of medicine Tianjin 300071China department of Medical oncology the Fifth Medical CenterGeneral Hospital of the Chinese People’s Liberation ArmyBeijing 100039China department of Medical oncology Xi'an Jiaotong UniversityXi’an 710061ShaanxiChina department of Pathology the Sixth Medical CenterGeneral Hospital of the Chinese People’s Liberation ArmyBeijing 100037China

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 *** Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study *** characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were ***-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low *** HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative *** were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

关键词： HER2 HER2-low Breast cancer Estrogen receptor Trastuzumab deruxtecan

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Microbiota in colorectal cancer related to liver metastasis

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Chinese Journal of Cancer Research 2024年第1期36卷 17-24页

作者： Peijun Wei Weiming Han Zitong Zhang Xue Tian Chen Yang Qiaoxuan Wang Weihao Xie Ying Liu Yuanhong Gao Hui Chang department of Radiation oncology State Key Laboratory of Oncology in South ChinaGuangzhou 510060China Guangdong Provincial Clinical Research Center for Cancer Guangzhou 510060China Sun Yat-sen University Cancer Center Guangzhou 510060China department of Pediatric oncology State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

The prevalence of colorectal cancer(CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum(F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately accelerating the onset and progression of CRC. However,little clinical evidence exists on the specific interplay between the gut microflora and colorectal cancer liver metastasis(CRLM). Some research showed the existence of viable F. nucleatum in distant metastasis of ***, gut microbiota products, such as lipopolysaccharides, sodium butyrate, and protein cathepsin K, were also found to affect the development of CRC. This article summarizes the mechanism and research status of the interplay between gut microflora and CRLM, discusses the importance of gut microflora in the treatment of CRLM, and proposes a new approach to understanding the mechanism of CRLM and potential treatments for the microbiome. It is anticipated that the gut microbiota will be a formidable therapeutic and prophylactic tool for treating and preventing CRLM.

关键词： Gut microbiota liver metastasis colorectal cancer

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A pilot study of precision treatment for patients with lung cancer pain by Longteng Tongluo recipe(龙藤通络方) using serum genomics

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Journal of Traditional Chinese medicine 2024年第5期44卷 1006-1016页

作者： WU Ruixin FANG Qingliang GUAN Sisi WEI Xianglong SHAN Mengjun MAO Zhujun GONG Yabin XU Ling ZHOU Di DONG Changsheng Preclinical department Shanghai Municipal Hospital of Traditional Chinese MedicineShanghai University of Traditional Chinese Medicine School of Traditional Chinese medicine Shanghai University of Traditional Chinese Medicine department of oncology Longhua HospitalShanghai University of Traditional Chinese Medicine department of oncology the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine department of oncology Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese Medicine Cancer Institute of Traditional Chinese medicine/department of oncology Longhua HospitalShanghai University of Traditional Chinese Medicine

OBJECTIVE: To investigate the efficacy of Longteng Tongluo recipe(龙藤通络方, LTTL) combined with threestep analgesia for the treatment of lung cancer pain, and the changes in serum miRNA expressions before-and after treatment with LTTL and its correlation with lung cancer pain. The possible mechanism underlying LTTL effects on the treatment of lung cancer pain was conducted. METHODS: The pilot study was conducted at the oncology ward of the Yueyang Hospital and the Longhua Hospital between March 2018 and October 2019. A prospective, single-blind, placebo controlled, randomized clinical trial of LTTL or placebo combined with three-step analgesia treatments were administered to 24 cancer pain patients diagnosed with lung cancer. Analgesic efficacy was investigated as the primary outcome. Equivalent morphine consumption and numerical rating scale(NRS) scores were used as the secondary outcome. In the present study, we utilized deep sequencing techniques to compare the differential miRNA expressions in serum samples obtained from two groups: the lung cancer pain treatment group(LTTL + three-step analgesia) and the control group(placebo + three-step analgesia). Next, we employed the target prediction database to investigate the target genes for differential miRNA expressions and Gene Ontology(GO) analysis along with Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis to examine the roles and the major biochemical and signaling pathways related to the differentially expressed target genes, respectively. RESULTS: LTTL treatment significantly reduces the NRS score(P = 0.021) as compared to those before treatment, along with significant reductions in the total morphine equivalent consumption(P = 0.007) and the average daily equivalent morphine consumption(P = 0.003) as opposed to the control group. The expressions of 31 miRNAs differed considerably between the two groups of patients( ≥ 2 times up-modulated or down-regulated between these groups, P < 0.05).

关键词： Longteng Tongluo recipe MicroRNA-chip Supporting information high-throughput nucleotide sequencing lung neoplasms neoplasm metastasis pain

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Inhibition of Ehrlich ascites carcinoma growth by melatonin:Studies with micro-CT

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oncology Research 2024年第1期32卷 175-185页

作者： SEHER YILMAZ ZÜLEYHA DOĞANYIĞIT MERT OCAK EVRIM SUNA ARIKAN SÖYLEMEZ ASLI OKAN OFLAMAZ SÜMEYYE UÇAR ŞÜKRÜATEŞ AMMAD AHMAD FAROOQI department of Anatomy Faculty of MedicineYozgat Bozok UniversityYozgatTurkey department of Mechanical and Aerospace Engineering Case Western Reserve UniversityClevelandOhioUSA department of Histology and Embriology Faculty of MedicineYozgat Bozok UniversityYozgatTurkey department of Anatomy Faculty of DentistryAnkara UniversityAnkaraTurkey department of Medical Biology Faculty of MedicineAfyonkarahisar Health Sciences UniversityAfyonTurkey department of Anatomy Faculty of MedicineErciyes UniversityKayseriTurkey department of Molecular oncology Institute of Biomedical and Genetic Engineering(IBGE)IslamabadPakistan

Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling *** has many benefits,such as organizing circadian rhythms and acting as a powerful *** aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous *** with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 *** measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and ***,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT *** the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control *** was determined that there was a significant decrease(p<0.05).Significant differences were found in the total AgNOR area/nuclear area(TAA/NA)ratio in the treatment groups(p<0.05).Furthermore,there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase(PI3K),AKT Serine/Threonine Kinase(PKB/AKT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell *** this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice *** characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advanc

关键词： Signaling pathway Apoptosis Real-time PCR AgNOR

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Transfer RNA-derived fragment tRF-23-Q99P9P9NDD promotes progression of gastric cancer by targeting ACADSB

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 438-450页

作者： Yu ZHANG Xinliang GU Yang LI Xun LI Yuejiao HUANG Shaoqing JU Medical School of Nantong University Nantong UniversityNantong 226001China department of Laboratory medicine Affiliated Hospital of Nantong UniversityNantong 226001China Research Center of Clinical medicine Affiliated Hospital of Nantong UniversityNantong 226001China department of Medical oncology Affiliated Hospital of Nantong UniversityNantong 226001China

Gastric cancer(GC)is one of the most common gastrointestinal *** a newly discovered type of non-coding RNAs,transfer RNA(tRNA)-derived small RNAs(tsRNAs)play a dual biological role in *** previous studies have demonstrated the potential of tRF-23-Q99P9P9NDD as a diagnostic and prognostic biomarker for *** this work,we confirmed for the first time that tRF-23-Q99P9P9NDD can promote the proliferation,migration,and invasion of GC cells in *** dual luciferase reporter gene assay confirmed that tRF-23-Q99P9P9NDD could bind to the 3'untranslated region(UTR)site of acyl-coenzyme A dehydrogenase short/branched chain(ACADSB).In addition,ACADSB could rescue the effect of tRF-23-Q99P9P9NDD on GC ***,we used Gene Ontology(GO),the Kyoto Encyclopedia of Genes and Genomes(KEGG),and Gene Set Enrichment Analysis(GSEA)to find that downregulated ACADSB in GC may promote lipid accumulation by inhibiting fatty acid catabolism and ***,we verified the correlation between ACADSB and 12 ferroptosis genes at the transcriptional level,as well as the changes in reactive oxygen species(ROS)levels by flow *** summary,this study proposes that tRF-23-Q99P9P9NDD may affect GC lipid metabolism and ferroptosis by targeting ACADSB,thereby promoting GC *** provides a theoretical basis for the diagnostic and prognostic monitoring value of GC and opens upnew possibilities for treatment.

关键词： Transfer RNA(tRNA)-derived small RNA(tsRNA) Gastric cancer(GC) Acyl-coenzyme A dehydrogenase short/branched chain(ACADSB) Molecular mechanism Treatment Ferroptosis

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Single-cell transcriptomics reveals tumor landscape in ovarian carcinosarcoma

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第8期25卷 686-699页

作者： Junfen XU Mengyan TU department of Gynecologic oncology Women’s HospitalZhejiang University School of MedicineHangzhou 310006China Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology Hangzhou 310006China

Objective:The present study used single-cell RNA sequencing(scRNA-seq)to characterize the cellular composition of ovarian carcinosarcoma(OCS)and identify its molecular ***:scRNA-seq was performed in resected primary OCS for an in-depth analysis of tumor cells and the tumor *** staining was used for *** scRNA-seq data of OCS were compared with those of high-grade serous ovarian carcinoma(HGSOC)tumors and other OCS ***:Both malignant epithelial and malignant mesenchymal cells were observed in the OCS patient of this *** identified four epithelial cell subclusters with different biological *** them,epithelial subcluster 4 presented high levels of breast cancer type 1 susceptibility protein homolog(BRCA1)and DNA topoisomerase 2-α(TOP2A)expression and was related to drug resistance and cell *** analyzed the interaction between epithelial and mesenchymal cells and found that fibroblast growth factor(FGF)and pleiotrophin(PTN)signalings were the main pathways contributing to communication between these ***,we compared the malignant epithelial and mesenchymal cells of this OCS tumor with our previous published HGSOC scRNA-seq data and OCS *** the epithelial subclusters in the OCS tumor could be found in the HGSOC ***,the mesenchymal subcluster C14 exhibited specific expression patterns in the OCS tumor,characterized by elevated expression of cytochrome P450 family 24 subfamily A member 1(CYP24A1),collagen type XXIIIα1 chain(COL23A1),cholecystokinin(CCK),bone morphogenetic protein 7(BMP7),PTN,Wnt inhibitory factor 1(WIF1),and insulin-like growth factor 2(IGF2).Moreover,this subcluster showed distinct characteristics when compared with both another previously published OCS tumor and normal ovarian ***:This study provides the single-cell transcriptomics signature of human OCS,which constitutes a new resource for elucidating OCS diversity.

关键词： Ovarian carcinosarcoma Single-cell RNA sequencing(scRNA-seq) Tumor heterogeneity

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Efficacy and safety of perioperative therapy for locally resectable gastric cancer:A network meta-analysis of randomized clinical trials

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World Journal of Gastrointestinal oncology 2024年第3期16卷 1046-1058页

作者： Zi-Yu Kuang Qian-Hui Sun Lu-Chang Cao Xin-Yi Ma Jia-Xi Wang Ke-Xin Liu Jie Li Graduate College Beijing University of Traditional Chinese MedicineBeijing 100029China oncology department Guang’anmen HospitalChina Academy of Chinese Medical SciencesBeijing 100053China

BACKGROUND Gastric cancer(GC)is the fifth most commonly diagnosed malignancy worldwide,with over 1 million new cases per year,and the third leading cause of cancer-related *** To determine the optimal perioperative treatment regimen for patients with locally resectable *** A comprehensive literature search was conducted,focusing on phase II/III randomized controlled trials(RCTs)assessing perioperative chemotherapy and chemoradiotherapy in treating locally resectable *** R0 resection rate,overall survival(OS),disease-free survival(DFS),and incidence of grade 3 or higher nonsurgical severe adverse events(SAEs)associated with various perioperative regimens were analyzed.A Bayesian network meta-analysis was performed to compare treatment regimens and rank their *** Thirty RCTs involving 8346 patients were included in this *** XELOX plus neoadjuvant radiotherapy and neoadjuvant CF were found to significantly improve the R0 resection rate compared with surgery alone,and the former had the highest probability of being the most effective option in this *** plus adjuvant FLOT was associated with the highest probability of being the best regimen for improving *** to limited data,no definitive ranking could be determined for *** nonsurgical SAEs,FLO has emerged as the safest treatment *** This study provides valuable insights for clinicians when selecting perioperative treatment regimens for patients with locally resectable *** studies are required to validate these findings.

关键词： Gastric cancer Perioperative treatment Network meta-analysis Efficacy and safety

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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

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