Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Abstract: The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 27236187
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: LUNG-CANCER ; VARIANTS ; BREAST-CANCER ; PROMOTER ; telomere length ; WIDE ASSOCIATION ; HTERT ; TERT-CLPTM1L LOCUS
    Abstract: Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
    Type of Publication: Journal article published
    PubMed ID: 23535824
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    ISSN: 1432-0800
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Glucose-induced insulin release is markedly decreased in the spontaneously diabetic Goto-Kakizaki (GK) rat pancreas. This defect was recently shown to be reversed by forskolin which markedly enhances cAMP generation in GK islets. These effects of forskolin were associated with overexpression of type-3 adenylyl cyclase (AC) mRNA due to the presence of two functional point mutations in the promoter region of AC3 gene in GK rat. Nine AC isoforms have been described, but their expression pattern in relation to the main pancreatic islet cell types, as well as their involvement in the diabetic state, is still unknown. Using antibodies raised against AC1–8, we have studied by double immunofluorescence the localisation of these AC isoforms in different endocrine cell types in both normal and diabetic GK rat pancreas. Our results demonstrated a clear immunoreaction (IR) to AC1–4 and 6 in normal and GK islet β-cells, while a smaller number of ACs were expressed in α- and δ-cells. No AC-IR was observed in pancreatic polypeptide cells. Moreover, we have found an increased IR of the Ca2+-stimulated AC1, AC3 and AC8 in diabetic β- and α-cells, compared with the corresponding IR in control pancreas. Most noticeable was the eliciting of a markedly enhanced AC8-IR in GK rat β- and α-cells, in contrast to a barely discernible AC8-IR in corresponding normal cells. In conclusion, AC expression exhibits a complex pattern in the endocrine pancreas, with specific differences between the normal and diabetic state.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    ISSN: 1432-0428
    Keywords: GK rats ; pancreatic islets ; liver ; FAD-linked glycerophosphate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In pancreatic islet extracts of rats with hereditary non-insulin-dependent diabetes mellitus (GK rats), the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase, as measured by either a radioisotopic or colorimetric procedure, only represented 30 to 40% of that found in control rats. This decrease in enzymic activity was not attributable to any sizeable change in either islet DNA content or the relative contribution of insulin-producing beta cells to total islet mass. It contrasted with a normal activity of other mitochondrial dehydrogenases and hexokinase isoenzymes. It coincided, however, with an increased activity of glutamate-pyruvate transaminase, as already observed in adult rats injected with streptozotocin during the neonatal period. The decreased activity of islet FAD-linked glycerophosphate dehydrogenase also contrasted with an increased activity of the same enzyme in the liver of GK, as compared to control rats. In the light of these findings and recent metabolic data collected in intact islets of GK rats, it is proposed that a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle, may represent a cause of inherited non-insulin-dependent diabetes.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    ISSN: 1090-6509
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Projectile multifragment breakup of 16O, 2C and 7Li at energies 3.0–4.5 A-GeV is studied by means of the Weizsäcker-Williams method. The fragmentation channels of the 16O projectile at 4.5 A-GeV are investigated and compared with that of 16O at 200 A-GeV. The events characterized by N h=0 and the events due to both Coulomb and diffraction dissociation have been selected and analyzed as a function of impact parameter. Also, the dependence of the electromagnetic dissociation cross-section on incident energy and the charge of projectile and target is found.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; pancreatic islets ; perfused pancreas ; glucose metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin secretion and islet glucose metabolism were compared in pancreatic islets isolated from GK/Wistar (GK) rats with spontaneous Type 2 (non-insulin-dependent) diabetes mellitus and control Wistar rats. Islet insulin content was 24.5±3.1 μU/ng islet DNA in GK rats and 28.8±2.5 μU/ng islet DNA in control rats, with a mean (±SEM) islet DNA content of 17.3±1.7 and 26.5±3.4 ng (p 〈 0.05), respectively. Basal insulin secretion at 3.3 mmol/l glucose was 0.19±0.03 μ · ng islet DNA−1· h−1 in GK rat islets and 0.40±0.07 in control islets. Glucose (16.7 mmol/l) stimulated insulin release in GK rat islets only two-fold while in control islets five-fold. Glucose utilization at 16.7 mmol/l glucose, as measured by the formation of 3H2O from [5-3 H]glucose, was 2.4 times higher in GK rat islets (3.1±0.7 pmol · ng islet DNA−1 · h−1) than in control islets (1.3±0.1 pmol · ng islet DNA−1 · h−1; p〈0.05). In contrast, glucose oxidation, estimated as the production of 14CO2 from [U-14C]glucose, was similar in both types of islets and corresponded to 15±2 and 30±3 % (p〈0.001) of total glucose phosphorylated in GK and control islets, respectively. Glucose cycling, i. e. the rate of dephosphorylation of the total amount of glucose phosphorylated, (determined as production of labelled glucose from islets incubated with 3H2O) was 16.4±3.4% in GK rat and 6.4±1.0% in control islets, respectively (p〈0.01). We conclude that insulin secretion stimulated by glucose is markedly impaired in GK rat islets. Glucose metabolism is also altered in GK rat islets, with diminished ratio between oxidation and utilization of glucose, and increased glucose cycling, suggesting links between impaired glucose-induced insulin release and abnormal glucose metabolism.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    ISSN: 1432-0428
    Keywords: Keywords Insulin ; arginine ; α-ketoisocaproate ; glibenclamide ; isobutylmethylxanthine ; isolated pancreatic islets ; perfused rat pancreas ; Goto-Kakizaki rat.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin responses to glucose and non-glucose secretagogues were studied in short-term cultured pancreatic islets and perfused pancreata of the glucose intolerant F1 hybrid rats of spontaneously diabetic Goto-Kakizaki and control Wistar rats. After culture at 5.5 mmol/l glucose, hybrid islet responses to 11.1, 16.7 and 27.0 mmol/l glucose were between 60 and 40 % of control islet responses. A combination of 1 mmol/l isobutylmethylxanthine and 16.7 mmol/l glucose induced a pronounced insulin release, which was of similar magnitude in hybrid and control rat islets. This response was not further augmented by addition of glibenclamide and arginine. The slope of potentiation of arginine (10 mmol/l)-stimulated insulin secretion by glucose (5.5–16.7 mmol/l) was greatly impaired in hybrid islets. In contrast to glucose, α-ketoisocaproate (KIC), which is metabolized in Krebs cycle, dose-dependently stimulated insulin secretion to similar levels in hybrid and control islets, cultured at 5.5 mmol/l glucose. Also in hybrid islets depolarized by potassium chloride (30 mmol/l) and with adenosine triphosphate-sensitive K+-channels kept open by diazoxide, insulin responses to glucose were greatly impaired but intact to KIC. Furthermore, KIC potentiated normally the insulin response to arginine in hybrid islets. In the isolated perfused pancreas, KIC induced similar insulin responses in hybrid rats and control rats. The potentiating effect by 5.5 mmol/l glucose on the KIC-stimulated insulin responses was, however, greatly reduced in isolated islets and absent in the perfused pancreata of hybrid rats. Taken together, these findings suggest an intact capacity for insulin release, although the initiating and potentiating effect by glucose on insulin release are defective in the Goto-Kakizaki-hybrid rats. An abnormal beta-cell glucose metabolism proximal to the Krebs cycle is likely to account for the impairment of insulin release. [Diabetologia (1998) 41: 1368–1373]
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    ISSN: 1434-601X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Photoemulsions were irradiated to 8.4, 9.6, 69 GeV/c protons and 4.2 GeV/c/nucleon12C ions. Large stars, having a number of heavily ionizing particlesn h≧28, were selected for this study. These events represent the catastrophic destruction of AgBr emulsion nuclei. Multiplicity, angular and energy distributions of particles, produced in this case, were studied at different momenta and for different incident particles. It was shown that the products of complete destruction of heavy nuclei are nearly individual nucleons. The probability of this phenomenon increases with the projectile mass number. About half of nuclear matter is knocked out of the target nucleus with energy higher than 30 MeV/nucleon. The average multiplicity ofs-particles¯n s is weakly dependent on the target nucleus mass number whereas the average multiplicity ofg-particles¯n g is strongly dependent on it. The modified pre-equilibrium model gives a satisfactory description for the energy spectrum of the emitted slow protons.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    ISSN: 1588-2780
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract Tin(IV) antimonate with different Sb/Sn molar ratios has been prepared. The characterization of the product materials was carried out using X-ray diffraction pattern, themal analysis and infrared spectra. The saturation capacities of sodium and cesium were found to increase with Sb/Sn molar ratios. TheK d values on thermal treatment of tin(IV) antimonate, as a cation exchanger, have been measured for some heavy metal ions in the temperature range of 50–400 °C. The maximum adsorption of 10−4M of the metal ions studied was obtained at 400 °C. The selectivity sequence was Eu3+〉Co2+〉Sr2+〉Cs+ for the sample heated up to 400 °C. No adsorption was observed on the sample heated at 700 °C because of the formation of SnO2 and Sb6O13.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...