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  • 1
    Abstract: Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16(INK4a), p21(CIP1) and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Emu-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 29258294
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  • 2
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO473 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  16. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie; 20091119-20091120; Berlin; DOC09gaa16 /20091105/
    Publication Date: 2009-11-06
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Medizinische Informatik, Biometrie und Epidemiologie; VOL: 4; DOC16 /20081028/
    Publication Date: 2008-10-29
    Keywords: health care ; veterinary ; quality management ; patient management ; mobile computing ; Gesundheitspflege ; tierärztlich ; Qualitätsmanagement ; Patientenmanagement ; Mobile Computing ; ddc: 610
    Language: German
    Type: article
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  • 5
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Backgound : Patients being investigated for symptoms of abdominal pain, diarrhoea and or weight loss often undergo small bowel radiology as part of their diagnostic workup mainly to exclude inflammatory bowel disease.Aim : To assess and compare the utility of a single faecal calprotectin estimation to barium follow through as well as conventional inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein in exclusion of intestinal inflammation.Methods : Seventy-three consecutive cases undergoing barium follow through for investigation of symptoms of diarrhoea and or abdominal pain with or without weight loss were studied. The control group comprised 25 cases with known active Crohn's disease (positive controls), 26 normal healthy volunteers (negative controls) and 25 cases of irritable bowel syndrome diagnosed by Rome II criteria. Symptoms, erythrocyte sedimentation rate and C-reactive protein were recorded at recruitment and a single stool sample assayed for calprotectin within 7 days prior to or after barium follow through.Results : The median calprotectin value in the active Crohn's group, irritable bowel syndrome group and normal volunteers was 227 μg/g of stool, 19 and 10 μg/g respectively (P 〈 0.0001). A faecal calprotectin above a cut-off value of 60 μg/g was able to predict all nine cases with an abnormal barium follow through as well as all six cases with a normal barium follow through but with organic intestinal disease. The negative predictive value of a single calprotectin result below 60 μg/g of stool was 100% compared with 91% each for erythrocyte sedimentation rate 〉 10 mm and C-reactive protein 〉 6 mg/L and 84% for a combination of erythrocyte sedimentation rate and C-reactive protein in predicting absence of organic intestinal disease.Conclusion : A single stool calprotectin value 〈 60 μg/g of stool obviates the need for further barium radiology of the small bowel, is more accurate than measurement of erythrocyte sedimentation rate or C-reactive protein and effectively excludes Crohn's disease or non-functional gastrointestinal disease.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1569-8041
    Keywords: high-dose chemotherapy ; poor prognosis germ-cell tumours
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The prognosis of patients with high-risk germ-cellcancer is poor. The toxicity and efficacy of first-line high-dose chemotherapy(HDCT) with stem-cell support was evaluated, following induction chemotherapywith BEP. Patients and methods:Twenty patients with poor prognosis nonseminomatous germ-cell tumour by the International Consensus prognosticcriteria received induction with BEP followed by one cycle of HDCT (CEC) givenwith carboplatin (1800 mg/m2), etoposide (1800 mg/m2),and cyclophosphamide (140 mg/kg). Of the above 20 patients only 3 received asecond cycle of HDCT. Peripheral blood stem cells were infused on day 0. Results:Twenty patients were assessable for toxicity andresponse. After a median follow-up of 27 months 15 patients (75%) arealive, 12 (60%) are disease free and 3 (15%) are alive withdisease. Median survival has not been reached and overall survival at fouryears is 66% with a durable complete response rate of 50%. Therewere no deaths or cases of severe toxicity. Median time to a granulocyte count〉500/µl and platelets 〉20,000/µl was 10 and 12 daysrespectively. Five patients have died from progressive disease 5–35months after HDCT. Conclusions:These results support the case of first-line HDCT.The excellent toxicity profile of BEP/CEC and the two-year overall survivalof 78% are encouraging and support further the ongoing randomised USintergroup study evaluating high-dose CEC after BEP.
    Type of Medium: Electronic Resource
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