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  • 1
    Keywords: EXPRESSION ; SURVIVAL ; CELL ; Germany ; KINASE ; imaging ; NEW-YORK ; PATIENT ; ACTIVATION ; MARKER ; prognosis ; QUALITY ; TYPE-1 ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; FIBER COMPOSITION ; BREAST-CANCER ; NO ; PERFORMANCE ; PLASMA ; AGE ; genetics ; FIBER ; MUSCLE ; PARAMETERS ; MORPHOLOGY ; SKELETAL-MUSCLE ; PREDICTION ; BODY ; POOR-PROGNOSIS ; heredity ; OXYGEN ; BIOPSY ; exercise ; MASSES ; BODIES ; REGRESSION ; INCREASE ; WEIGHT ; LIFE ; PHYSICAL-ACTIVITY ; HEIGHT ; QUALITY-OF-LIFE ; LEVEL ; MYOPATHY ; PLASMA-LEVELS ; technique ; USA ; LOSSES ; uptake ; correlation ; cachexia ; myopathies ; PREDICT ; BIOPSIES ; INCREASES ; - ; RESONANCE ; CANCER DIAGNOSIS ; TRACK ; FOXO TRANSCRIPTION FACTORS ; cancer cachexia ; muscle biopsy ; muscle morphology ; muscle wasting
    Abstract: Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r=0.65, p 〈 0.001) and to the CSA fraction formed by type 1 and 2a fibers (r=0.80, p 〈 0.001). However, when adjusted for body height and age by multiple regression, MG yielded a largely improved prediction of total CSA (multiple r=0.83, p 〈 0.001) and of fiber type 1 and 2a CSA (multiple r=0.89, p 〈 0.001). The correlations between CK and these muscle parameters were weaker, and elevated CK values were observed in 20% of control subjects despite a prior abstinence from exercise for 5 days. In conclusion, plasma MG, when adjusted for anthropometric parameters unaffected by weight, may be considered as a novel marker of muscle mass (CSA) indicating best the mass of MG-rich type 1 and 2a fibers as well as VO(2)max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study
    Type of Publication: Journal article published
    PubMed ID: 17605115
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  • 2
    Keywords: IN-VIVO ; CANCER-THERAPY ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; WILD-TYPE P53 ; INHIBITORS ; RESTORATION ; SUPPRESSOR FUNCTION ; SMALL-MOLECULE ANTAGONISTS ; MDM2 ANTAGONISTS ; NEUROECTODERMAL TUMOR
    Abstract: Medulloblastomas account for 20% of pediatric brain tumors. With an overall survival of 40%-70%, their treatment is still a challenge. The majority of medulloblastomas lack p53 mutations, but even in cancers retaining wild-type p53, the tumor surveillance function of p53 is inhibited by the oncoprotein MDM2. Deregulation of the MDM2/p53 balance leads to malignant transformation. Here, we analyzed MDM2 mRNA and protein expression in primary medulloblastomas and normal cerebellum and assessed the mutational status of p53 and MDM2 expression in 6 medulloblastoma cell lines. MDM2 expression was elevated in medulloblastomas, compared with cerebellum. Four of 6 medulloblastoma cell lines expressed wild-type p53 and high levels of MDM2. The tumor-promoting p53-MDM2 interaction can be inhibited by the small molecule, nutlin-3, restoring p53 function. Targeting the p53-MDM2 axis using nutlin-3 significantly reduced cell viability and induced either cell cycle arrest or apoptosis and expression of the p53 target gene p21 in these 4 cell lines. In contrast, DAOY and UW-228 cells harboring TP53 mutations were almost unaffected by nutlin-3 treatment. MDM2 knockdown in medulloblastoma cells by siRNA mimicked nutlin-3 treatment, whereas expression of dominant negative p53 abrogated nutlin-3 effects. Oral nutlin-3 treatment of mice with established medulloblastoma xenografts inhibited tumor growth and significantly increased survival. Thus, nutlin-3 reduced medulloblastoma cell viability in vitro and in vivo by re-activating p53 function. We suggest that inhibition of the MDM2-p53 interaction with nutlin-3 is a promising therapeutic option for medulloblastomas with functional p53 that should be further evaluated in clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 22591662
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  • 3
    Keywords: pediatrics ; medulloblastoma ; cell proliferation ; pediatric ; PATHWAY ; VITRO ; Germany ; CELL ; CELL-PROLIFERATION ; proliferation ; IN-VITRO ; ACTIVATION ; p53
    Type of Publication: Meeting abstract published
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  • 4
    Keywords: INHIBITOR ; SURVIVAL ; Germany ; KINASE ; MODEL ; SITE ; SITES ; PROTEIN ; COMPLEX ; COMPLEXES ; MECHANISM ; FAMILY ; BINDING ; ACID ; CATALYTIC SUBUNIT ; DESIGN ; PROSTATE-CANCER ; DERIVATIVES ; ATP ; CRYSTAL-STRUCTURE ; PROTEIN-KINASES ; EXCHANGE ; SERIES ; TARGETS ; AKT ; INHIBITORS ; PROGRAM ; AMINO-ACID ; MUTANTS ; BALANOL ; KINASES ; MOLSCRIPT
    Abstract: Protein kinase B (PKB)-selective inhibitors were designed.. synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase),PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very Similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures. and binding studies were performed to rationalize the selectivity and improve the design
    Type of Publication: Journal article published
    PubMed ID: 15634010
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  • 5
    ISSN: 1432-0983
    Keywords: Podospora anserina ; ATP synthase subunit 9 ; Nucleotide sequence ; Nuclear localisation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The nuclear gene coding for the mitochondrial subunit 9 of the F0F1-ATP synthase complex was isolated from a genomic library of Podospora anserina. Nucleotide sequencing revealed an open reading frame capable to code for 144 amino acids including an amino-terminal pre-sequence of 63 amino acid residues for mitochondrial import of the pre-proteolipid. The P. anserina proteolipid shows extensive sequence identity with the corresponding gene products of the related filamentous fungi Neurospora crassa, Aspergillus nidulans and Aspergillus niger. In contrast to the situation in Saccharomyces cerevisiae, N. crassa and A. nidulans, no sequence similarity of the ATP synthase subunit 9 gene to the mitochondrial genome of P. anserina could be detected. Thus, in P. anserina this gene appears to be exclusively encoded by the nuclear genome.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pest science 22 (1949), S. 33-37 
    ISSN: 1612-4766
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung Es wird über die Bestimmung der 1-Phosphofructalaldoalse und der Sorbitdehydrogenase berichtet. Beide Methoden sind zur Differentialdiagnose Hepatitis-Verschlußikterus gut geeignet, wobei wir der 1-Phosphofructalaldolase den Vorzug geben. Sie können den bisher üblichen Methoden besonders bei der Diagnose der Hepatitis mit Verschlußsyndrom überlegen sein. Nach unserer Erfahrung gelingt die Abgrenzung der chronischen Hepatitis von den harmlosen Hyperbilirubinämien durch die Bestimmung der genannten Enzyme nicht. Der Vorteil der Bestimmung dieser Fermente liegt in ihrer weitgehenden Leberspezifität und in der Tatsache, daß sie im normalen Serum fast nicht vorkommen.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Behavioral ecology and sociobiology 37 (1995), S. 385-391 
    ISSN: 1432-0762
    Keywords: Communal suckling ; Cavies ; Birth synchrony ; Multi-litter mixing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We quantified the extent of communal suckling in the cavy Galea musteloides. Six groups of animals were held in large indoor enclosures and suckling behavior was recorded over 113 h of observation. The groups contained 2–6 lactating females and 3–14 sucking pups. Due to the relative synchronization of births, 73% of the pups present in each group during lactation were non-offspring. Each of the 22 lactating females in the six groups suckled non-offspring in addition to her own offspring. On average, females suckled 86% of non-offspring present in their groups. Thus, 98% of all pups (n = 47) received milk from non-mothers. Although suckling frequencies were significantly higher for mothers with their own individual offspring than with non-offspring individuals, females invested more total time suckling all non-offspring than did suckling just their own; this was possible because for each mother many more non-offspring than offspring pups were present during lactation. Suckling bouts were significantly longer for mothers with their own individual offspring than with non-offspring individuals. The proportion of non-offspring suckling of mothers correlated negatively with the proportion of own young among the pups of a group. Non-offspring suckling did not affect future reproduction of females. Our observations demonstrate extensive practice of communal suckling in G. musteloides under laboratory conditions. Probably because all mothers of a group participated more or less equally in communal suckling behavior, the obvious cost of giving energetically expensive milk to non-offspring did not result in reduced (future) reproductive success. Potential benefits directly involved with communal suckling are unclear. More indirectly, communal suckling as well as birth synchrony might contribute to the formation of advantageous multi-litter kindergardens.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Behavioral ecology and sociobiology 37 (1995), S. 385-391 
    ISSN: 1432-0762
    Keywords: Key words Communal suckling ; Cavies ; Birth synchrony ; Multi-litter mixing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We quantified the extent of communal suckling in the cavy Galea musteloides. Six groups of animals were held in large indoor enclosures and suckling behavior was recorded over 113 h of observation. The groups contained 2–6 lactating females and 3–14 sucking pups. Due to the relative synchronization of births, 73% of the pups present in each group during lactation were non-offspring. Each of the 22 lactating females in the six groups suckled non-offspring in addition to her own offspring. On average, females suckled 86% of non-offspring present in their groups. Thus, 98% of all pups (n = 47) received milk from non-mothers. Although suckling frequencies were significantly higher for mothers with their own individual offspring than with non-offspring individuals, females invested more total time suckling all non-offspring than did suckling just their own; this was possible because for each mother many more non-offspring than offspring pups were present during lactation. Suckling bouts were significantly longer for mothers with their own individual offspring than with non-offspring individuals. The proportion of non-offspring suckling of mothers correlated negatively with the proportion of own young among the pups of a group. Non-offspring suckling did not affect future reproduction of females. Our observations demonstrate extensive practice of communal suckling in G. musteloides under laboratory conditions. Probably because all mothers of a group participated more or less equally in communal suckling behavior, the obvious cost of giving energetically expensive milk to non-offspring did not result in reduced (future) reproductive success. Potential benefits directly involved with communal suckling are unclear. More indirectly, communal suckling as well as birth synchrony might contribute to the formation of advantageous multi-litter kindergardens.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1618-2650
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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