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Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

World Journal of Gastroenterology 2018年第48期24卷 5418-5432页

作者： sandra Wagner christina s mullins Michael Linnebacher section of Molecular Oncology and Immunotherapy General SurgeryUniversity Medical Center

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

关键词： Cancer vaccines Colorectal neoplasm Immunotherapy Neoplasm antigen tumor-associated antigens tumor-specific antigens Neoantigen(s)

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Mouse models of colorectal cancer: Past, present and future perspectives

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World Journal of Gastroenterology 2020年第13期26卷 1394-1426页

作者： Florian Bürtin christina s mullins Michael Linnebacher Department of General VisceralVascular and Transplantation SurgeryUniversity Medical Center RostockUniversity of RostockRostock 18057Germany Department of Thoracic surgery University Medical Center RostockUniversity of RostockRostock 18057Germany Molecular Oncology and Immunotherapy Department of GeneralVisceralVascular and Transplantation SurgeryUniversity Medical Center RostockRostock 18057Germany

Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United states as well as in the European *** the incidence and mortality rates in western,high developed countries are declining,reflecting the success of screening programs and improved treatment regimen,a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development *** a growing insight into the biology of CRC and many therapeutic improvements in the recent decades,preclinical in vivo models are still indispensable for the development of new treatment *** the development of carcinogen-induced rodent models for CRC more than 80 years ago,a plethora of animal models has been established to study colon cancer *** tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related *** engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or *** the vast majority of CRC GEMM lack invasiveness,metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses;thus,supporting development of new therapeutic *** of metastatic disease by orthotopic injection of CRC cell lines is possible,but the so generated models lack genetic diversity and the number of suited cell lines is very ***-derived xenografts,in contrast,maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development–even in comparison to GEMM or cell line-based ***,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor micr

关键词： Colorectal cancer Mouse models Patient-derived xenografts Carcinogen-induced models Genetically engineered mouse models Preclinical drug development

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A global assessment of recent trends in gastrointestinal cancer and lifestyle-associated risk factors

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Cancer Communications 2021年第11期41卷 1137-1151页

作者： Lili Lu christina s.mullins Clemens schafmayer sebastian Zeißig Michael Linnebacher Department of General surgery Molecular Oncology and ImmunotherapyRostock University Medical CenterRostock 18057Germany Department of Medicine I University Hospital Carl Gustav CarusTechnische Universität(TU)DresdenDresden 01307Germany

Background:Gastrointestinal(GI)cancers were responsible for 26.3%of cancer cases and 35.4%of deaths worldwide in *** study aimed to analyze the global incidence,mortality,prevalence,and contributing risk factors of the 6 major GI cancer entities[esophageal cancer(EC),gastric cancer(GC),liver cancer(LC),pancreatic cancer(PC),colon cancer,and rectal cancer].Methods:Using the Global Cancer Observatory and the Global Health Observatory databases,we reviewed the current GI cancer incidence,prevalence,and mortality,analyzed the association of GI cancer prevalence with national human development indices(HDIs),identified the contributing risk factors,and estimated developing age-and sex-specific trends in incidence and ***:In 2020,the trend in age-standardized rate of incidence of GI cancers closely mirrored that of mortality,with the highest rates of LC,EC,and GC in Asia and of colorectal cancer(CRC)and PC mainly in *** and mortality were positively,but the mortality-to-incidence ratio(MIR)was inversely correlated with the national HDI *** MIRs in developing countries likely reflected the lack of preventive strategies and effective *** cancer prevalence was highest in Europe and was also positively correlated with HDIs and lifestyle-associated risk factors,such as alcohol consumption,smoking,obesity,insufficient physical activity,and high blood cholesterol level,but negatively correlated with hypertension and *** of EC were consistently and those of GC mostly decreasing,whereas incidences of CRC were increasing in most countries/regions,especially in the younger *** of LC and PC were also increasing in all age-gender populations except for younger *** were decreasing for EC,GC,and CRC in most countries/regions, and age-specific trends were observed in PC and LC with adecrease in the younger but an increase in the older ***: On the global scale, higher GI c

关键词： annual percentage change(APC) diabetes gastrointestinal(GI)cancer high blood cholesterol human development indices(HDI) hypertension incidence lifestyle mortality prevalence

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Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

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World Journal of Gastrointestinal surgery 2022年第5期14卷 383-396页

作者： Meng Dai christina s mullins Lili Lu Guido Alsfasser Michael Linnebacher Clinic of General surgery Molecular Oncology and ImmunotherapyRostock University Medical Center18057 RostockGermany Clinic of General surgery Rostock University Medical Center18057 RostockGermany

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive *** incidence has increased over the last *** specific pathogenetic mechanisms underlying GEP-NEN development have not been completely *** GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of ***,many GEP-NEN patients present with later staged *** hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent *** result of which is great progress in clinical diagnosis and *** to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell *** different functional imaging methods facilitates precise *** expression of somatostatin receptors helps to predict *** analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(sMAD 4)help distinguishing grade 3 NENs from poorly differentiated *** aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.

关键词： GEP-NENs Functional imaging Peptide receptor radionuclide therapy Targeting agents Immune checkpoint inhibitors Genetic mutations

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Human endogenous retroviruses and cancer:Causality and therapeutic possibilities

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World Journal of Gastroenterology 2012年第42期18卷 6027-6035页

作者： christina s mullins Michael Linnebacher Department of General ThoracicVascular and Transplantation SurgerySection Molecular Oncology and ImmunotherapyUniversity of RostockSchillingallee 3518057 RostockGermany

A substantial part of the human genome is derived from transposable elements;remnants of ancient retroviral *** estimates set the percentage of human endogenous retroviruses(HERVs) in the genome at 8%.For the most part,the interplay between mutations,epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic *** first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and *** has been shown that at least in some cases,tumor cells expressing HERV open reading frames(ORFs) thus gain tumor-promoting ***,since these proteins are not expressed in healthy tissues,they become prime target *** potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' *** from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity *** development of new tumor(immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side ***,we postulate on main future research streams in order to stimulate discussion on this hot topic.

关键词： Human endogenous retroviruses Gastro-intestinal cancer Therapeutic targets Tumor-specificantigens Tumorigenesis

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Establishment,functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line

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World Journal of Gastroenterology 2018年第33期24卷 3749-3759页

作者： Michael Gock christina s mullins Christine Harnack Friedrich Prall Robert Ramer Anja Goder Oliver H Kramer Ernst Klar Michael Linnebacher Department of General surgery University of RostockRostock 18055Germany Department of General surgery Section of Molecular Oncology and ImmunotherapyUniversity of RostockRostock 18055Germany Institute of Pathology University of RostockRostock 18055Germany Institute of Pharmacology University of RostockRostock 18055Germany Institute of Toxicology University Medical Center MainzMainz 55131Germany

AIM To establish cell line and patient-derived xenograft(PDX) models for neuroendocrine carcinomas(NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research includingbiomarker testing and drug response *** Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue(HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting(i.e., sTR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid *** The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a Cp G island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAs(wt), BRAF(mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUsION We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

关键词： Patient-derived tumor model Large cell neuroendocrine carcinoma Individualized medicine

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Establishment,functional and genetic characterization of three novel patient-derived rectal cancer cell lines

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World Journal of Gastroenterology 2018年第43期24卷 4880-4892页

作者： Michael Gock christina s mullins Carina Bergner Friedrich Prall Robert Ramer Anja Goder Oliver H Kramer Falko Lange Bernd J Krause Ernst Klar Michael Linnebacher Department of General surgery University Medical CenterRostock 18055Germany section of Molecular Oncology and Immunotherapy University MedicalCenterRostock 18055Germany Department of NuclearMedicine University Medical CenterRostock 18055Germany Institute of Pathology University MedicalCenterRostock 18055Germany Institute of Pharmacology University Medical CenterRostock 18055Germany Institute of Toxicology University Medical Center MainzMainz 55131Germany Oscar-Langendorff-Institute of Physiology University Medical CenterRostock 18055Germany

AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy *** Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 *** We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MsI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAs^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAs^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAs^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all th

关键词： Patient-derived tumor model Rectal cancer ^(18)F-fluorodeoxyglucose ^(18)F-fluorothymidine FOLFOX FOLFIRI Personalized medicine

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胃肠道癌症和生活方式风险因素的近期趋势的全球评估

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癌症 2022年第7期41卷 308-323页

背景与目的2018年,胃肠道(gastrointestinal,GI)癌症占全球癌症病例的26.3%和癌症死亡人数的35.4%。本研究旨在分析全球6种主要胃肠道癌症:食道癌(esophageal cancer,EC)、胃癌(gastric cancer,GC)、肝癌(liver cancer,LC)、胰腺癌(pancreatic cancer,PC)、结肠癌(colon cancer,CC)和直肠癌(rectal cancer,RC)的发病率、死亡率、患病率和致病风险因素。方法我们使用全球癌症观察站(Global Cancer Observatory,GCO)和全球卫生观察站(Global Health Observatory,GHO)数据库,回顾当前的GI癌症发病率、患病率和死亡率,分析GI癌症患病率与国家的人类发展指数(human development indices,HDI)的相关性,确定致病风险因素,估计不同年龄和性别人群的发病率和死亡率的发展趋势。结果2020年,GI癌症年龄标化发病率趋势与死亡率密切相关,LC、EC和GC的发病率在亚洲最高,结直肠癌(colorectal cancer,CRC)和PC的发病率在欧洲较高。发病率和死亡率呈正相关,而死亡发病比(mortalityto-incidence ratio,MIR)与国家HDI水平呈负相关。发展中国家的高MIR可能反映了预防战略和有效治疗的缺乏。GI癌症在欧洲较常见,与HDI和生活方式相关风险因素,如饮酒、吸烟、肥胖、运动不足和高血胆固醇水平等呈正相关,但与高血压和糖尿病呈负相关。在大多数国家/地区,EC的发病率一直在下降,GC的发病率也多呈下降趋势,而CRC的发病率却在上升,特别是在年轻人群中。除年轻男性外,LC和PC的发病率在所有年龄和性别的人群中也都在上升。在大多数国家/地区,EC、GC和CRC的死亡率都在下降,在PC和LC中观察到了年龄特定趋势:在年轻人口中减少,在老年人口中增加。结论在全球范围内,较高的GI癌症负担在很大程度上伴随着所谓的西方生活方式相关因素,这些因素反映了高和非常高的国家人类发展指数水平。在HDI非常高的国家/地区,患者生存时间更长,但随着国家HDI水平的提高,GI癌症患者也在增加。因此,我们建议优化GI癌症预防策略和改进治疗方案,尤其是对合并代谢性疾病的患者。

关键词：年度变化百分比(APC) 糖尿病胃肠道癌症(GI) 高血脂人类发展指数(HDI) 高血压发病率生活方式死亡率患病率

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A toast to a zebrafish germ cell induction cocktail

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science China(Life sciences) 2024年第6期67卷 1314-1315页

作者： Mary C.mullins Department of Cell and Developmental Biology University of Pennsylvania Perelman School of MedicinePhiladelphia 19104USA

The zebrafish field is ringing in the new year with a publication from Yonghua sun's laboratory(Wang et al.,2023)of a cocktail of germline factors that can induce all cells of the zebrafish embryo into primordial germ cells(PGCs)at phenomenal *** major advance is not only of great interest to germ cell biologists,but it has important applications to the entire zebrafish field,as shown in Wang et al.(2023).

关键词： fish zebra field

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soil Temperature Dependent Growth of Cotton seedlings Before Emergence

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Pedosphere 2008年第1期18卷 54-59页

作者： G.NABI C.E.mullins Land Resources Research Program National Agricultural Research CentrePark RoadIslamabad45500 (Pakistan) Department of Plant and soil science Cruickshank BuildingUniversity of AberdeenAB24 3UU (UK)

soil temperature is an important variable governing plant growth and development. studies were conducted under laboratory conditions to determine the effect of soil temperature on root and shoot growth of cotton during emergence. Cotton seedlings were grown for 192 h at 20, 32 and 38℃ in soil packed in 300 mm long and 50 mm diameter cylinders. The data indicated that the longest roots （173 ram） as well as shoots （152 mm） were recorded at 32℃ followed by 20 （130 mm root and 82 mm shoot） and 38℃ （86 mm root and 50 mm shoot）. Roots grown at 20 and 38 ℃ were 20% and 50% shorter, respectively, than those grown at 32℃ after 192 h. Roots and shoots exhibited the lowest length and dry biomass at 38 ℃. shoot lengths grown at 20 （74 mm） and 38℃（51 mm） were 44% and 61% shorter than those grown at 32℃（131 mm） after 180 h growth period, respectively. Growth at all three temperatures followed a similar pattern. Initially there was a linear growth phase followed by the reduction or cessation of growth. Time to cessation of growth varied with temperature and decreased faster at higher temperatures. sowing of cotton should be accomplished before seedbed reaches a soil temperature （≥ 38 ℃） detrimental for emergence. Further, the seedbeds should be capable of providing sufficient moisture and essential nutrients for emerging seedling before its seed reserves are exhausted to enhance seedling establishment in soil.

关键词： linear growth root/shoot elongation soil temperature

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