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| 1 | The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines显示文摘AIM: There are conflicting data about p53 function on cellular sensitivity to the cytotoxic action of 5-fluorouracil (5-FU).Therefore the objective of this study was to determine the combined effects of adenovirus-mediated wild-type (wt) p53 gene transfer and 5-FU chemotherapy on pancreatic cancer cells with different p53 gene status.METHODS: Human pancreatic cancer cell lines Capan-1^p53mut,Capan-2^p53wt, FAMPAC^p53mut, PANG1^p53mut, and rat pancreatic cancer cell lines AS^p53wt and DSL6A^p53null were used for in vitro studies. Following infection with different ratios of Adp53-particles (MOI) in combination with 5-FU, proliferation of tumor cells and apoptosis were quantified by cell proliferation assay (WST-1) and FACS (PI-staining). In addition, DSL6A syngeneic pancreatic tumor cells were inoculated subcutaneously in to Lewis rats for in vivostudies.Tumor size, apoptosis (TUNEL) and survival were determined.RESULTS: Ad-p53 gene transfer combined with 5-FU significantly inhibited tumor cell proliferation and substantially enhanced apoptosis in all four cell lines with an alteration in the p53 gene compared to those two cell lines containing wt-p53. In vivo experiments showed the most effective tumor regression in animals treated with Ad-p53 plus 5-FU. Both in vitroand in vivoanalyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by 5-FU.CONCLUSION: Our results suggest that Ad-p53 may synergistically enhance 5-FU-chemosensitivity most strikingly in pancreatic cancer cells lacking p53 function. These findings illustrate that the anticancer efficacy of this combination treatment is dependent on the p53 gene status of the target tumor cells. | Sven Eisold Michael Linnebacher EduardRyschich DaliborAntolovic UlfHinz Ernst Klar Jan Schmidt | 2004 | World Journal of Gastroenterology2004，10，24： | 14 |
| 2 | Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens显示文摘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. | Sandra Wagner Christina S Mullins Michael Linnebacher | 2018 | World Journal of Gastroenterology2018，24，48： | 10 |
| 3 | Mouse models of colorectal cancer: Past, present and future perspectives显示文摘Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union.While 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 index.Despite 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 approaches.Since 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 biology.Despite tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis.Genetically engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited.Although 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 avenues.Induction 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 limited.Patient-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 analyses.However,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses.The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models. | Florian Bürtin Christina S Mullins Michael Linnebacher | 2020 | World Journal of Gastroenterology2020，26，13： | 9 |
| 4 | A global assessment of recent trends in gastrointestinal cancer and lifestyle-associated risk factors显示文摘Background:Gastrointestinal(GI)cancers were responsible for 26.3%of cancer cases and 35.4%of deaths worldwide in 2018.This 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 mortality.Results: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 Europe.Incidence and mortality were positively,but the mortality-to-incidence ratio(MIR)was inversely correlated with the national HDI levels.High MIRs in developing countries likely reflected the lack of preventive strategies and effective treatments.GI 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 diabetes.Incidences of EC were consistently and those of GC mostly decreasing,whereas incidences of CRC were increasing in most countries/regions,especially in the younger populations.Incidences of LC and PC were also increasing in all age-gender populations except for younger males.Mortalities 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 population.Conclusions: On the global scale, higher GI cancer burden was accompanied,for the most part, by factors associated with the so-called Western lifestylereflected by high and very high national HDI levels. In countries/regionswith very high HDI levels, patients survived longer, and increasing GI cancercases were observed with increasing national HDI levels. Optimizing GI cancer prevention and improving therapies, especially for patients with comorbidmetabolic diseases, are thus urgently recommended. | Lili Lu Christina S.Mullins Clemens Schafmayer Sebastian Zeißig Michael Linnebacher | 2021 | Cancer Communications2021，41，11： | 6 |
| 5 | Human endogenous retroviruses and cancer:Causality and therapeutic possibilities显示文摘A substantial part of the human genome is derived from transposable elements;remnants of ancient retroviral infections.Conservative 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 cells.We 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 therapy.It has been shown that at least in some cases,tumor cells expressing HERV open reading frames(ORFs) thus gain tumor-promoting functions.However,since these proteins are not expressed in healthy tissues,they become prime target structures.Of potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' activities.Evidence 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 boundaries.The 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 effects.Finally,we postulate on main future research streams in order to stimulate discussion on this hot topic. | Christina S Mullins Michael Linnebacher | 2012 | World Journal of Gastroenterology2012，18，42： | 4 |
| 6 | Bacteriolytic therapy of experimental pancreatic carcinoma显示文摘AIM:To investigate the effectiveness of Clostridium novyi(C.novyi)-NT spores for the treatment of established subcutaneous pancreatic tumor in the syngeneic,immunocompetent Panc02/C57Bl/6 model. METHODS:C.novyi-NT spores were applied intravenously to animals carrying established pancreatic tumors of three different sizes.Systemic immune responses in peripheral blood and spleen were examined by flow cytometry.Supplementary,cytotoxic activity of lymphocytes against syngeneic tumor targets was analyzed. RESULTS:Application of spores identified,that(1) small tumors(<150 mm 3 )were completely unaffected (n=10);(2)very large tumors(>450 mm3)responded with substantial necrosis followed by shrinkage and significant lethality most likely due to tumor lysis syndrome (n=6);and(3)an optimal treatment window exists for tumors of approximately 250 mm 3 (n=21).In this latter group,all tumor-bearing animals had complete tu-mor regression and remained free of tumor recurrence. In subsequent tumor rechallenge experiments a significant delay in tumor growth compared to the initial tumor cell inoculation was observed(tumor volume at day 28:197.8±87.3 mm 3 vs 500.1±50.9 mm3,P<0.05). These effects were accompanied by systemic activation of immune response mechanisms predominantly mediated by the innate arm of the immune system. CONCLUSION:The observed complete tumor regression is encouraging and shows that immunotherapy with C.novyi-NT is an interesting strategy for the treatment of pancreatic carcinomas of defined sizes. | Claudia Maletzki Michael Gock Ulrike Klier Ernst Klar Michael Linnebacher | 2010 | World Journal of Gastroenterology2010，16，28： | 3 |
| 7 | Intranasal immunization with human papillomavirus type 16 capsomeres in the presence of non-toxic cholera toxin-based adjuvants elicits increased vaginal immunoglobulin levels 显示文摘 | Dell K Koesters R Linnebacher M | 2006 | Vaccine2006，24，： | 1 |
| 8 | Generation of RAGE I and MAGE-9 peptide-specific cytotoxie T-lymphocyte lines for transfer in patients with renal cell earcinoma显示文摘 | Oehlrich N Devitt G Linnebacher M | 2005 | Int J Cancer2005，117，2： | 1 |
| 9 | Frameshift-derived neoantigens constitute immunotherapeutic targets for patients with microsatellite-instable haematological malignancies显示文摘 | Claudia Maletzki Fabian Schmidt Wilhelm G. Dirks Michael Schmitt Michael Linnebacher | 2013 | European Journal of Cancer2013，，11： | 1 |
| 10 | Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers显示文摘 | Yvette Schwitalle Matthias Kloor Susanne Eiermann Michael Linnebacher Peter Kienle Hanns Peter Knaebel Mirjam Tariverdian Axel Benner Magnus von Knebel Doeberitz | 2008 | Gastroenterology2008，，4： | 1 |
| 11 | Induction of protective immunity against syngeneic rat cancer cells by expression of the cytosine deaminase suicide gene 显示文摘 | Hsack K Linnebacher M Eisold S | 2000 | Cancer Gene Ther2000，7，10： | 1 |
| 12 | Chromosomally and mi- crosatellite stable eoloreetal carcinomas without the CpG island methylator pbenotype in a molecular classification 显示文摘 | Ostwald C Linnebacher M Weirich V | 2009 | Int J Oneol2009，35，2： | 1 |
| 13 | Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNTCC - associated cancers, but without hematological malignancy and brain tumor显示文摘 | Plaschke J Linnebacher M Kloor M | 2006 | European Journal of Human Genetics2006，14，5： | 1 |
| 14 | Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms显示文摘Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According 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 NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic 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 NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs. | Meng Dai Christina S Mullins Lili Lu Guido Alsfasser Michael Linnebacher | 2022 | World Journal of Gastrointestinal Surgery2022，14，5： | 1 |
| 15 | Induction of Protective Immunity Against Syngeneic Rat Cancer Cells by Expression of the Cytosine Deaminase Suicide Gene显示文摘 | Haack K Linnebacher M Eisold S | 2000 | Cancer Gene Ther2000，7，10： | 1 |
| 16 | Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens显示文摘 | Linnebacher M Gebert J Rudy W | 2001 | Int J Cancer2001，93，1： | 1 |
| 17 | Reevaluating the Concept of Treating Experimental Tumors with a Mixed Bacterial Vaccine: Coley’s Toxin显示文摘 | C. Maletzki U. Klier W. Obst B. Kreikemeyer M. Linnebacher Y. Yoshikai | 2012 | Clinical and Developmental Immunology2012，，： | 1 |
| 18 | Impact of portal branch ligation on tissue regeneration, microcirculatory response and microarchitecture in portal blood-deprived and undeprived liver tissue显示文摘 | Michael Gock Christian Eipel Michael Linnebacher Ernst Klar Brigitte Vollmar | 2011 | Microvascular Research2011，，3： | 1 |
| 19 | Intranasal immunization with human papillomavirus type 16 capsomeres in the presence of non toxic cholera toxin-based adjuvants elicits increased vaginal immunoglobulin levels 显示文摘 | Dell K Koesters R Linnebacher M | 2006 | Vaccine2006，24，13： | 1 |
| 20 | Generation of highly pure fusions of colorectal carcinoma and antigen-presenting cells显示文摘 | Ulrike Klier Claudia Maletzki Ernst Klar Michael Linnebacher | 2010 | Langenbeck’s Archives of Surgery2010，，4： | 1 |
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