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  • 1
    Keywords: B-CELLS ; radiation sensitivity ; DOUBLE-STRAND BREAKS ; GEL-ELECTROPHORESIS ; BREAST-CANCER PATIENTS ; alkaline comet assay ; NORMAL TISSUE COMPLICATIONS ; H2AX PHOSPHORYLATION ; INDUCED DNA-DAMAGE ; LYMPHOBLASTOID CELL-LINES
    Abstract: Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.
    Type of Publication: Journal article published
    PubMed ID: 23110060
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; CELL ; Germany ; VITRO ; COHORT ; DEATH ; SAMPLES ; LINES ; PATIENT ; CELL-LINES ; SUSCEPTIBILITY ; INDUCED APOPTOSIS ; B-CELLS ; PERIPHERAL-BLOOD ; cell lines ; EPSTEIN-BARR-VIRUS ; immortalization ; HYPERSENSITIVITY ; ionising radiation ; 33 ; Lymphoblastoid cell lines ; ATAXIA-TELANGIECTASIA PATIENTS ; DOCUMENTATION ; HUMAN LYMPHOCYTE SUBPOPULATIONS ; Individual radiosensitivity ; Multicentric trial ; PHOSPHATIDYLSERINE
    Abstract: In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable
    Type of Publication: Journal article published
    PubMed ID: 19142732
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; radiotherapy ; PATHWAY ; TOXICITY ; COHORT ; GENE ; GENE-EXPRESSION ; radiation ; MESSENGER-RNA ; mechanisms ; BREAST-CANCER ; LYMPHOCYTES ; CANCER-PATIENTS ; EPSTEIN-BARR-VIRUS ; Epstein-Barr virus ; ONCOLOGY ; immortalization ; BLOOD-CELLS ; Individual radiosensitivity ; Ionizing irradiation ; LYMPHOBLASTOID CELL-LINES ; mRNA expression ; White blood cell subtypes
    Abstract: The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6h after in vitro irradiation with 5Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. Expression was also measured in lymphocyte subpopulations and Epstein-Barr transformed lymphocytes. Radiation response in whole lymphocyte populations was most similar to that of B cells. In peripheral blood lymphocytes of all patients; 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. The signatures of radio-responsive genes differed tremendously between primary and transformed cells. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. The classifying potential of the expression signature has now to be validated in further patient cohorts.
    Type of Publication: Journal article published
    PubMed ID: 21236564
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  • 4
  • 5
    Keywords: STAGE ; OXALIPLATIN ; REGIMENS ; chemoradiation ; PREOPERATIVE RADIOTHERAPY ; ADJUVANT THERAPY ; III TRIAL ; METASTATIC COLORECTAL-CANCER ; LEUCOVORIN ; POSTOPERATIVE CHEMORADIOTHERAPY
    Abstract: BACKGROUND: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50.4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50.4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12.5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0.0004; post-hoc test for superiority p=0.05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0.07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0.67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0.04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [〈1%] grade 3-4 vs ten [5%], one [〈1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING: Roche Pharma AG (Grenzach-Wyhlen, Germany).
    Type of Publication: Journal article published
    PubMed ID: 22503032
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  • 6
    ISSN: 1432-0878
    Keywords: Diptera ; Spermiogenesis ; Nuclear condensation ; Accessory membranes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Description / Table of Contents: Zusammenfassung Querschnitte durch Spermatiden von Coelopa frigida zeigen ungewöhnliche Membranstrukturen. Diese Membranen treten in jungen Spermatiden zunächst als zusätzliche Membranschichten an zwei gegenüberliegenden Sciten der Kernmembran auf. Mit fortschreitender Spermienreifung rollen die Enden der Membranen ein, so daß sie das Erscheinungsbild eines Querschnittes durch eine Schriftrolle (scroll) geben. Die Funktion dieser Struktur ist unbekannt, möglicherweise ist sie an der Verdichtung des Chromatins beteiligt. Eine zweite Struktur, die in C. frigida stärker ausgeprägt ist als in anderen Dipteren, ist eine extranukleäre, granuläre Masse in engem Kontakt mit den Zentriolen. Eine Öffnung in der Kernmembran scheint Materialaustausch zwischen dieser Masse und dem Kerninneren zu ermöglichen.
    Notes: Summary Membranes of unknown functions are observed in transverse sections of developing spermatids of Coelopa frigida. These membranes appear as accessory layers of the nuclear envelope of young spermatids. The end regions of the accessory membranes curl up to form a scroll-like structure as the spermatid matures. Two scroll-like structures are found in all spermatids. The scroll-like structure could be involved in nuclear condensation. A second structure, the eentriolar adjunct in the posterior region of the nucleus is in direct contact with the chromatin during its condensation. A gap in the nuclear membrane seems to facilitate the passage of material between the nucleus and the centriolar adjunct.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0044-2313
    Keywords: Rhenium complexes ; carbonyl complexes ; nitrosyl complexes ; heptamethylindene ; crystal structures ; σ/η-bonding ; Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Syntheses of Metal Carbonyls. 23. Crystal Structure and Reactivity of Heptamethylindenyl Carbonyl Metal ComplexesReaction of heptamethylindene (C9(CH3)7, 1) with Re2(CO)10 yields [η5-C9(CH3)7]Re(CO)3 (2), which reacts with NO+BF4- to form the cationic complex [{η5-C9(CH3)7}Re(CO)2NO]+BF4- (3). Irradiation of 2 with UV light in the presence of triethyl phosphite leads to formation of [η5-C9(CH3)7]Re(CO)2[P(OC2H5)3] (4). Alkylation of (CH3)3SnCl with Ind*Li gives [η1-C9(CH3)7]Sn(CH3)3 (5). All compounds were characterized by spectroscopic methods. The molecular structures of 3 and 5 were determined by single crystal X-ray diffraction (3: P21/n (14), a = 1497.7(4) pm, b = 879.0(2) pm, c = 1609.0(4) pm and β = 110.99(2)°, R1 = 0.038, wR2 = 0.080; 5: P21/n (14), a = 726.1(1) pm, b = 2930.7(3) pm, c = 930.0(1) pm and β = 112.834(5)°, R1 = 0.044, Rw = 0.048). Complexes 2-4 exhibit a piano stool configuration with a η5-coordinated permethylindenyl ligand (Ind*). Compound 5 displays a η1 -coordination of the Ind* ligand. Temperature enhancement causes a hapticity change, as observed by NMR spectroscopy.
    Notes: Heptamethylinden (C9(CH3)7H, 1) reagiert mit Re2(CO)10 zu [η5-C9(CH3)7]Re(CO)3 (2), das durch Umsetzung mit NO+BF4- die kationische Verbindung[{η5-C9(CH3)7}Re (CO)2NO]+BF4- (3) und unter Bestrahlung mit UV-Licht in Anwesenheit von Triethylphosphit [η5-C9(CH3)7]Re(CO)2[P(OC2H5)3] (4) ergibt. Durch Alkylierung von (CH3)3SnCl wird [η1-C9(CH3)7]Sn(CH3)3 (5) erhalten. Alle Verbindungen wurden mit spektroskopischen Methoden vollständig charakterisiert. Von 3 und 5 wurden die Kristallstrukturen röntgenstrukturanalytisch bestimmt (3: P21/n (14), a = 1497.7(4) pm, b = 879.0(2) pm, c = 1609.0(4) pm und β = 110.99(2)°, R1 = 0.038, wR2 = 0.080; 5: P21/n (14), a = 726.1(1) pm, b = 2930.7(3) pm, c = 930.0(1) pm und β = 112.834(5)°, R1 = 0.044, Rw = 0.048). Während bei den Komplexen 2-4 der Heptamethylindenligand (Ind*) einen Halbsandwich-Komplex bildet (η5-Bindung zum Metall), so liegt in Derivat 5 erwartungsgemäß eine σ-Bindung zwischen einem C-Atom des Ind*-Liganden und dem Metallzentrum vor. Bei Temperaturerhöhung tritt eine Änderung der Haptizitätsverhältnisse ein (NMR-Evidenz).
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 8
  • 9
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    ISSN: 0365-9496
    Keywords: Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1434-601X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract. For improved measurements of the key astrophysical reaction 12C(α,γ)16O in inverted kinematics, a recoil separator ERNA is being developed at the 4 MV Dynamitron tandem accelerator in Bochum to detect directly the 16O recoils with about 50% efficiency. Calculations of the ion beam optics including all filtering and focusing elements of ERNA are presented. Since the 12C projectiles and the 16O recoils have essentially the same momentum, and since the 12C ion beam emerging from the accelerator passes through a momentum filter (analysing magnet), the 12C ion beam must be as free as possible from 16O contamination for ERNA to succeed. In the present work, the 16O contamination was reduced from a level of 1 × 10−11 to a level below 2 × 10−29 by the installation of Wien filters both before and after the analysing magnet. The measurement of these and other beam specifications involved other parts of the final ERNA layout – sequentially a Wien filter, a 60˚ dipole magnet, another Wien filter, and a ΔE-E telescope. The setup led to a measured suppression factor of 5 × 10−18 for the 12C ion beam. The experiments also indicate that an almost free choice of the charge state for the 16O recoils is possible in the separator.
    Type of Medium: Electronic Resource
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