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Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

Science China Life Sciences 2025年第1期68卷 144-157页

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing Key Laboratory of Carcinogenesis and translational Research (Ministry of Education/Beijing) Division of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute Department of Gastrointestinal Cancer Center Peking University Cancer Hospital & Institute Department of Liver Surgery & Transplantation Liver Cancer InstituteZhongshan HospitalFudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDivision of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

关键词： extrachromosomal DNA cancer therapy tumor heterogeneity drug resistance tumor evolution

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T cell responses to hepatitis B surface antigen are detectable in non-vaccinated individuals

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World Journal of Gastroenterology 2008年第16期14卷 2529-2533页

作者： Martin R Weihrauch Michael von Bergwelt-Baildon Milos Kandic Martin Weskott Winfried Klamp Joachim Rsler Joachim L Schultze Molecular tumor Biology and tumor immunology University of Cologne Gesundheitsschutz Wuppertaler Stadtwerke AG Department for Occupational Health University of Cologne

AIM: To evaluate, whether humoral hepatitis-B-vaccine non-responders also fail to mount a T cell response and to compare these results to normal vaccinees. METHODS: Fourty-seven health care employees were enrolled in this study including all available non- responders (n = 13) with an anti-HBsAg titer group) with titers > 1000 kU/L as controls. PBMC from all subjects were analyzed by IFN-γ and IL-4 ELISPOT assays for the presence of hepatitis B surface antigen (HBsAg) reactive T cells. RESULTS: Non-responders and low-responders had no or only very limited T cell responses, respectively. Indi- viduals responding to vaccination with the induction of a high anti-HBsAg titer showed a strong T cell response after the third vaccination. Surprisingly, these individuals showed response even before the first vaccination. T cell response to control antigens and mitogens was similar in all groups. CONCLUSION: Our data suggest that there is no gen- eral immune deficiency in non-/low-responders. Thus, we hypothesize that the induction of anti-HBsAg re- sponses by vaccination is significantly dependent on the pre-existing T cell repertoire against the specific antigen rather than the presence of a general T cell defect.

关键词： Hepatitis B T cell Non-responder Vaccination

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Overall expression of beta-catenin outperforms its nuclear accumulation in predicting outcomes of colorectal cancers

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World Journal of Gastroenterology 2008年第39期14卷 6052-6059页

作者： Worrawit Wanitsuwan Samornmas Kanngurn Teeranut Boonpipattanapong Rassamee Sangthong Surasak Sangkhathat tumor Biology Research group and Department of Surgery Faculty of MedicinePrince of Songkla UniversityThailand tumor Biology Research group and Department of Pathology Faculty of MedicinePrince of Songkla UniversityThailand tumor Biology Research group and Epidemiology Unit Faculty of MedicinePrince of Songkla UniversityThailand

AIM： To examine the expression of beta-catenin in colorectal cancer and look for association with other dinico-pathological parameters. METHODS;： tumor samples from 163 cases of colorectal cancer （CRC） who had undergone primary colectomy between May, 1998 and November, 2002 with complete follow-up data for either 5 years or until death were recruited for a beta-catenin immunohistochemical study. The percentage of immunoreacted tumor cells was defined as overall staining density （OSD） and percentage of cells having nuclear localization was counted as nuclear staining density （NSD）. Univariate exploration used log-rank test and multivariate survival analysis used Cox＇s hazard regression model. RESULTS： Beta-catenin immunoreactivity was detected in 161 samples （98.8%）, of which 131 cases had nuclear staining. High OSD （≥ 75%）, detected in 123 cases （75.5%）, was significantly associated with earlier clinical staging （P 〈 0.01）, lower nodal status （P = 0.02）, non-metastatic status （P 〈 0.01） and better differentiation （P = 0.02）. Multivariate analysis found that high OSD was independently associated with better survival [Cox＇s hazard ratio 0.51, 95% confidence interval （CI） 0.31-0.83]. Although high NSD （≥ 75%） was correlated with high pre-operative serum CEA （P = 0.03）, well differentiation （P 〈 0.01）, and increased staining intensity（P 〈 0.01）, the parameter was not significantly associated with survival. CONCLI3SIOM： Unlike previous reports, the study did not find a predictive value of nuclear beta-catenin in CRC. Instead, the overall expression of beta-catenin in CRC showed an association with better differentiation and earlier staging. Moreover, the parameter also independently predicted superior survival.

关键词： Colorectal carcinoma beta-catenin CTNNB1 Wnt-signaling pathway Prognosis

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Clinicopathologic features of 112 cases with mantle cell lymphoma

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Cancer Biology & Medicine 2015年第1期12卷 46-52页

作者： Dong-Mei Zhou Gang Chen Xiong-Wei Zheng Wei-Feng Zhu Bao-Zhen Chen Department of Pathology Key Laboratory of Cancer Translational Medicine of FujianTeaching Hospital of Fujian Medical UniversityFujian Tumor Hospital

Objective： This study aims to explore the clinicopathologic features of 112 patients with mantle cell lymphoma （MCL）. Methods： Data from 112 MCL cases were collected, and immunohistochemical assay was conducted. Fluorescence in situ hybridization （FISH） detected a break in the CCND 1 gene. The t-test was used in the statistical analysis. Results： All tumor cells in the 112 cases expressed B cell-related antigen, including 1 blastoid subtype and 1 polymorphic subtype. Among all cases, 106 expressed CD5 and 104 expressed cyclin D1. A break in the CCND1 gene was not found in 3 cases with CDS-MCL. IgH/CCND 1 polyploid was observed in 2 classic cases. Conclusion： MCL is a type of special immunophenotypic B-cell lymphoma, The prognoses ofblastoid and polymorphic subtypes are poor. Special subtypes should be classified during diagnosis.

关键词： Mantle cell lymphoma (MCL) immunohistochemistry fluorescence in situ hybridization (FISH) prognosis

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Anterior mediastinal masses and thymic cysts

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World Journal of Clinical Cases 2025年第4期13卷 1-7页

作者： ÖnerÖzdemir Department of Pediatric Allergy and immunology Sakarya Research and Training HospitalSakarya University Medical FacultyAdapazarı54100SakaryaTürkiye

Cystic lesions of the anterior mediastinum in children suggest a well-known group of benign lesions that are comparatively *** cysts(TCs)are mostly positioned in the anterior mediastinum and some patients in the *** TCs classified as congenital intra-thoracic mesothelial cysts are commonly asymptomatic and have slight clinical *** TC,which can mimic another anterior mediastinal cystic tumor and is seen in adults,is more clinically *** is a sporadic mediastinal lesion thought to arise in the course of acquired *** mediastinal cysts represent 3%-6%of all mediastinal tumors and 10%-18%of radiologically reported mediastinal *** TCs are uncommon and it is hard to know their true *** 60%of cases with mediastinal TCs are asymptomatic,and the remainder of patients complains of nonspecific symptoms(e.g.,chest pain,dyspnea,or cough).The literature suggests that most cysts are benign,but an indefinite percentage may have a neoplastic process and result in significant compressive symptoms over *** symptoms of TCs vary depending on the *** addition,frequent symptoms at the appearance of enlarged benign thymic and mediastinal cysts generally contain compressive symptoms(e.g.,respiratory distress,thymic pain,and symptoms related to Horner syndrome,hoarseness,dysphonia,dyspnea,orthopnea,wheezing,and fever).Many TCs have cystic density and a neat border and are simple to diagnose with radiological ***,some TCs are hard to identify before surgery and may be misidentified as thymomas depending on their site and computed tomography *** by thoracotomy,median sternotomy,or video-assisted techniques is essential for conclusive diagnosis,management,and abolition of relapse of anterior mediastinal masses and *** examination may be required after *** the extent of the mass and the preliminary inability to make a definitiv

关键词： Mediastinal mass Thymic cyst Malignant tumor Cysts Thymoma Computer tomography

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Immune characteristics analysis reveals two key inflammatory factors correlated to the expressions of SARS-CoV-2 S1-specific antibodies

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Genes & Diseases 2022年第2期9卷 522-530页

作者： Shenglong Li Wang Wang Tingting Li Xiaojian Han Chao Hu Yingming Wang Meiying Shen Li Du Yaru Nai Jianwei Wang Aishun Jin Department of immunology College of Basic MedicineChongqing Medical UniversityChongqing 400016PR China Chongqing Key Laboratory of Basic and translational Research of tumor immunology Chongqing Medical UniversityChongqing 400016PR China Department of Breast Surgery Harbin Medical University Cancer HospitalHarbin 150081PR China

The pandemic of COVID-19 caused by SARS-CoV-2 has made serious threats to the public *** have been considered as promising therapeutics for the prevention and treatment of *** far,effectors that can influence the sustainability of SARS-CoV-2 specific antibodies in COVID-19 patients are still *** this paper,we attempted to find potential key factors correlated with SARS-CoV-2 specific *** analysis with the peripheral blood mononuclear cells(PBMCs)revealed proportional changes of immune cell subsets in COVID-19 convalescent patients,including a substantial decrease of monocytes and evident increase of dendritic cells(DCs).Moreover,we found that the gene expressions of chemokines associated with monocyte/macrophage were significantly up-regulated during the COVID-19 recovery *** importantly,we found a set of 27 immune genes corresponding to a comparatively lower amount of SARS-CoV-2 specific antibodies,and identified two hub genes,IL1βand IL6,the protein expressions of which exhibited negative correlation with the immunoglobulin G(IgG)levels in COVID-19 convalescent *** addition,we found that high expressions of these 2 hub genes during the convalescent stage were negatively associated with the plasma cell marker *** study presented two key inflammatory factors correlated to the low level of SARS-CoV-2 specific antibodies,which indicated the potential regulatory process of plasmatic antibodies levels in some COVID-19 convalescent patients.

关键词： Antibodies Convalescent stage COVID-19 Cytokines IL1b and IL6

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Antigen presentation,autoantibody production,and therapeutic targets in autoimmune liver disease

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Cellular & Molecular immunology 2021年第1期18卷 92-111页

作者： Andrea Kristina Horst Kingsley Gideon Kumashie Katrin Neumann Linda Diehl Gisa Tiegs Institute of Experimental immunology and Hepatology University Medical Center Hamburg-EppendorfMartinistraBe 52D-20251 HamburgGermany Hamburg Center for translational immunology University Medical Center Hamburg-EppendorfMartinistraBe 52D-20251 HamburgGermany

The liver is an important immunological organ that controls systemic *** liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and *** the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment,which Is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating *** response to pathogens or autoantigens,tolerance is disrupted by unknown *** parenchymal and nonparenchymal cells exhibit unique antigen-presenting *** presentation of microbial and endogenous lipid-,metabolite-and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or *** of this balance results in autoimmune liver diseases,such as autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing *** the exact etiologies of these autoimmune liver diseases are unknown,it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids,as well as alterations in bile acid composition,may result in changes in effector cell activation and polarization and may reduce or impair protective antiinflammatory regulatory T and B cell ***,the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different(non)immune cells in the liver may play a role in the induction of hepatic inflammation and ***,we summarize emerging aspects of antigen presentation,autoantibody production,and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.

关键词： liver tolerance autoimmune liver disease antigen presentating cell

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Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer

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World Journal of Gastrointestinal Oncology 2023年第8期15卷 1349-1365页

作者： Noel E Donlon Maria Davern Andrew Sheppard Fiona O'Connell Brendan Moran Timothy S Nugent Aisling Heeran James J Phelan Anshul Bhardwaj Christine Butler Narayanasamy Ravi Claire L Donohoe Niamh Lynam-Lennon Stephen Maher John V Reynolds Joanne Lysaght Cancer immunology and Immunotherapy group Department of SurgeryTrinity Translational Medicine Institute and Trinity St James’s Cancer InstituteTrinity College DublinSt James’s HospitalDublin D08Ireland

BACKGROUND There is an intimate crosstalk between cancer formation,dissemination,treatment response and the host immune system,with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer ***,inducing a purposeful synergistic response between conventional therapies and the immune system remains *** release of damage associated molecular patterns(DAMPs)is indicative of immunogenic cell death and propagation of established immune ***,there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma(OAC)or by immune cells *** To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic *** We investigated the levels of immunogenic cell death-associated DAMPs,calreticulin(CRT)and HMGB1 using an OAC isogenic model of *** expression was also assessed directly using ex vivo cancer patient T cells(n=10)and within tumour biopsies(n=9)both pre and post-treatment with clinically relevant chemo(radio)*** Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in *** increased frequencies of T cell DAMP expression in OAC patients were observed following chemo-(radio)therapy,which was significantly higher in tumour tissue compared with peripheral *** with high expression of HMGB1 had a significantly better tumour regression grade(TRG 1-2)compared to low *** In conclusion,OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors,which correlated with tumour regression grade and lymphatic *** also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

关键词： Damage associated molecular patterns HMGB1 Calreticulin Oesophageal adenocarcinoma T cells Radiation

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Human adipose, placenta, and umbilical cord-derived mesenchymal stem cells ameliorate imiquimod-induced psoriatic mice via reducing T cells infiltration

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BIOCELL 2021年第3期45卷 537-546页

作者： JIGANG LEI ZHENYAO XU SUKE LI MENG LI ZHIKAI WANG PING LI JING WANG YINGLU CHEN X IAOLE SONG CHENGJIE REN MEIPING SHEN CHENGXIANG DAI Cellular Biomedicine group Shanghai200233China translational Medicine Center Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai200025China Shanghai Institute of immunology Shanghai Jiaotong University School of MedicineShanghai200025China

Psoriasis is an autoimmune-related chronic inflammatory disease with an approximate prevalence of 2–3%around the world,involving increased keratinocyte ***,Th17 cells and IL-17 play critical roles in the pathogenesis of *** monoclonal antibodies against cytokines have been shown to have effectively immunosuppressive effects on human ***,there are still some patients that have no response to these *** patients have even serious side-effects which may affect their *** stem cells have the ability of immunosuppressive and anti-inflammatory effects,which may be an alternative therapy with more safety and efficacy for human ***,the underlying mechanisms by which the MSCs prevent or ameliorate psoriasis are still poorly ***,we first isolated and characterized human adipose,placenta,and umbilical cord-derived mesenchymal stem cells(haMSCs,hpMSCs,and huMSCs).After that,the animal model of imiquimod(IMQ)-induced psoriasis in C57BL/6 mice was *** investigated the impact of haMSCs,hpMSCs,and huMSCs on this model by H&E staining,immunohistochemistry staining,and quantitative real-time *** analysis showed that mice subcutaneously injected with these MSCs had a significantly decreased epidermal thickness,which was caused by obviously reduced hyper-proliferation of ***,our findings revealed that the infiltration of T cells to psoriatic lesions in IMQ-induced psoriasis mice was markedly downregulated by intradermal administration of haMSCs,hpMSCs,and huMSCs,***,the production of IL-17 from Th17 cells was reduced,which inhibits the proliferation of keratinocytes in lesioned skin of IMQ-induced psoriasis *** data suggest that haMSCs,hpMSCs,and huMSCs can inhibit the effects of proinflammatory Th17 cells on the development of psoriasis,which may be potential therapeutic candidates for skin inflammatory disease or other autoimmune

关键词： Mesenchymal stem cells Psoriasis T cells Skin inflammation Cell therapy

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The PI3K/Akt/m TOR pathway in ovarian cancer: therapeutic opportunities and challenges

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Chinese Journal of Cancer 2015年第1期34卷 4-16页

作者： Bianca Cheaib Aurélie Auguste Alexandra Leary Gynecological Unit Department of MedicineGustave Roussy Comprehensive Cancer Centre Gynecological tumor Team Translational Research Laboratory U981 Gustave Roussy Comprehensive Cancer Centre

The phosphatidylinositol 3 kinase(PI3K) pathway is frequently altered in cancer, including ovarian cancer(OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin(m TOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective m TOR complex-1(m TORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual m TORC1/m TORC2, Akt, and PI3 K inhibitors. Although it is likely that inhibition of the PI3K/Akt/m TOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha(PIK3CA) and/or phosphatase and tensin homolog(PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3 K signaling network, PI3 K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3 K pathway in OC and provide an up-to-date review of clinical trials of novel PI3 K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

关键词： mTOR 信号通路卵巢癌磷脂酰肌醇3激酶 AKT 激素疗法治疗临床试验

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