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  • 1
    Keywords: IN-VIVO ; C-JUN ; PROTEIN-KINASE ; BREAST-CANCER ; CARCINOMA-CELLS ; ACTIVATING TRANSCRIPTION FACTOR-2 ; MELANOMA-CELLS ; ESOPHAGEAL ADENOCARCINOMA ; SUPEROXIDE-DISMUTASE EXPRESSION ; CYCLIN-A PROMOTER
    Abstract: Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress-based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21(WAF1) , but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21(WAF1) protein expression, suggesting p21(WAF1) transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2-binding sequence in the p21(WAF1) promoter. p-ATF2 was found to interact with p-c-Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21(WAF1) downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4-dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti-cancer therapies.
    Type of Publication: Journal article published
    PubMed ID: 23800081
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Gastrointestinal symptoms are the most common side-effects of tegaserod therapy. In data pooled from Phase III randomized controlled trials in patients with irritable bowel syndrome with constipation, diarrhoea was reported by 8.8% of patients treated with tegaserod 6 mg b.d. vs. 3.8% of patients treated with placebo. Similar rates were observed in international post-US marketing randomized controlled trials. In most patients, tegaserod-induced diarrhoea was mild and transient. In randomized controlled trials, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of irritable bowel syndrome patients discontinued tegaserod due to diarrhoea. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea and flatulence) was similar in tegaserod-treated and placebo-treated patients. Pooled analysis of Phase III and post-US marketing randomized controlled trials did not demonstrate significant differences between tegaserod-treated and placebo-treated patients in the incidence of abdominal/pelvic surgery. No episodes of ischaemic colitis were reported in tegaserod-using patients in any Phase III or post-marketing randomized controlled trials, and post-marketing surveillance indicated that the rate of ischaemic colitis in tegaserod-using patients was lower than that in non-tegaserod-using patients. Pooled analysis of Phase III randomized controlled trials demonstrated an increase in the incidence of headaches in tegaserod-treated (6 mg b.d.) vs. placebo-treated patients (15% vs. 12.3%, respectively; P 〈 0.05), although post-US marketing randomized controlled trials did not demonstrate this increase. Other extra-gastrointestinal adverse events occurred with similar frequency in tegaserod-treated and placebo-treated patients. Tegaserod-treated patients in randomized controlled trials did not demonstrate significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. In summary, tegaserod exhibits a favourable safety and tolerability profile in irritable bowel syndrome patients based on data from clinical trials.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To quantify, through systematic review, the epidemiology and natural history of Crohn’s disease in North America.〈section xml:id="abs1-2"〉〈title type="main"〉Methods:The selected articles contained: (i) population-based samples of patients followed from the time of diagnosis; and (ii) objective diagnostic criteria for disease. Studies on the natural history of Crohn’s disease also contained sufficient follow-up.〈section xml:id="abs1-3"〉〈title type="main"〉Data collection and analysis:For prevalence studies, data on the incidence, prevalence, gender and age at diagnosis were extracted. For natural history studies, data on the disease activity, use of medications and surgery were extracted.〈section xml:id="abs1-4"〉〈title type="main"〉Main results:The prevalence of Crohn’s disease in North America ranges from 26.0 to 198.5 cases per 100 000 persons. The incidence rates range from 3.1 to 14.6 cases per 100 000 person-years. Most patients have a chronic intermittent disease course, while 13% have an unremitting disease course and 10% have a prolonged remission. Less than half require corticosteroids at any point. During any given year, approximately 10% are treated with corticosteroids and 30% are treated with 5-aminosalicylates. Up to 57% of patients require at least one surgical resection.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Between 400 000 and 600 000 patients in North America have Crohn’s disease, and the natural history is marked by frequent exacerbations requiring treatment with corticosteroids, 5-aminosalicylate products and surgery.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-5217
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Description / Table of Contents: Zusammenfassung In dieser Arbeit wird das bekannte, derLegendre-Transformation nachgebildete Konzept der nichtlinearen Dualität auf das allgemeine Vektor-Maximum-Problem übertragen. Hierbei wird die Dualität der Zielmengen (nicht aber der zulässigen Lösungen) des primalen und dualen Programms untersucht. Die Struktur der Zielmengen wird eingehend studiert. Hauptergebnis ist, daß unter plausiblen Regularitätsbedingungen keine „Lücken” zwischen der primalen und der dualen Zielmenge auftreten.
    Notes: Summary In this paper the well-knownLegendre transform-type of non-linear duality is extended to the general vector maximum problem. Duality is studied in terms of the primal and dual objective sets rather than in terms of the underlying feasible solutions. The structure of the objective sets is fully explored. The main result in duality is that under reasonable regularity assumptions there are no duality gaps between the primal and dual objective sets.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background:  The natural history of irritable bowel syndrome is unclear, including the likelihood that these patients will be diagnosed with an alternative organic or functional gastrointestinal disorder. Understanding the stability of an irritable bowel syndrome diagnosis may limit repeated diagnostic evaluation among these patients.Methods:  The inclusion criteria included observational longitudinal studies of clinic-based samples of adult patients with irritable bowel syndrome. Only studies published in the English language in full manuscript form were included. Literature searches, selection and review of eligible articles, and data abstraction were performed in a duplicate, independent manner.Results:  Fourteen studies met study selection criteria. In six studies with relevant information, 2–5% of irritable bowel syndrome patients were diagnosed with an alternative organic GI disorder after 6 months to 6 years of follow-up. Long-term follow-up indicated that 2–18% of patients developed worse irritable bowel syndrome symptoms, approximately 30–50% of patients had unchanged symptoms, and the rest either improved or had symptoms disappear. Prior surgery (one study), higher somatic scores (one study), higher baseline anxiety (two studies), depression scores (one study) were predictive of worsening of symptoms during long-term follow-up.Conclusions:  Irritable bowel syndrome, a chronic disorder, is a stable diagnosis. Once initial investigations are negative, fewer than 5% are diagnosed with an alternative organic GI disorder. Repeated diagnostic evaluations of patients with recurrent or persistent symptoms similar to their baseline symptoms are not warranted.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background : In the USA, tegaserod is contraindicated in patients with a history of bowel obstruction, abdominal adhesions or symptomatic gall-bladder disease due to a non-significant difference in abdominal surgery between tegaserod-using and placebo-using patients in Phase III trials.Aim : To calculate the incidence of abdominal and pelvic surgery in tegaserod-using and placebo-using patients in randomized controlled trials and to assess the possible association between medication and surgery, using pre-specified criteria in a blind adjudication procedure.Methods : Primary study selection criteria included: (i) randomized controlled trial; (ii) comparison of tegaserod vs. placebo; and (iii) results reporting the incidence of abdominal and pelvic surgery. A panel of experts in epidemiology and functional bowel disorders reviewed the history of each patient who underwent surgery. Experts were blind with regard to whether patients used tegaserod or placebo. Using pre-specified criteria, experts rated the likelihood of an association between medication use and surgery.Results : Thirteen randomized controlled trials (n =9857 patients) met the primary study selection criteria. No significant difference in the incidence of abdominal/pelvic surgery was identified between tegaserod-using and placebo-using patients: pelvic surgery, 0.16% vs. 0.19% (P = 0.80); abdominal surgery (non-cholecystectomy), 0.15% vs. 0.19% (P = 0.61); cholecystectomy, 0.13% vs. 0.03% (P = 0.17); total abdominal/pelvic surgery, 0.44% vs. 0.41% (P = 1.00). Post-adjudication, there was no significant difference in the incidence of abdominal/pelvic surgery between tegaserod-using and placebo-using patients.Conclusion : Data from randomized controlled trials demonstrate a similar incidence of abdominal/pelvic surgery in tegaserod-using and placebo-using patients.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aim : To systematically review research on the prevalence of abdominal and pelvic surgery in patients with irritable bowel syndrome.Methods : Computer searches of MEDLINE, EMBASE and Current Contents were performed independently by both investigators to identify appropriate studies. Primary study selection criteria included: (i) population-based samples of adult irritable bowel syndrome patients; (ii) the use of appropriate symptom-based criteria to identify irritable bowel syndrome patients; and (iii) comparison of the prevalence of abdominal and pelvic surgery in irritable bowel syndrome patients vs. control populations. Secondary analysis was performed on published studies of referral populations and case series.Results : Two population-based studies met the primary study selection criteria and revealed an increased prevalence of surgery in irritable bowel syndrome patients vs. controls for cholecystectomy (4.6% vs. 2.4%, respectively; odds ratio, 1.9; 95% confidence interval, 1.2–3.2) and hysterectomy (18% vs. 12%, respectively; odds ratio, 1.6; 95% confidence interval, 1.1–2.2). Secondary analysis revealed an increased prevalence of appendectomy and other abdominal and pelvic surgery in irritable bowel syndrome patients.Conclusions : Irritable bowel syndrome is associated with a disproportionately high prevalence of abdominal and pelvic surgery, but most studies exhibit sub-optimal study design and do not define the factors causing the increased prevalence of surgery in these patients.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aim : To assess the effectiveness and safety of budesonide in comparison to corticosteroids, 5-aminosalicylic acid (5-ASA), or placebo for inducing remission of active Crohn's disease and for maintaining remission.Study selection criteria : Randomized controlled trials comparing budesonide to corticosteroids, 5-ASA products or placebo were included. Trials had to report on the effectiveness of treatment (defined as decreasing or maintaining Crohn's Disease Activity Index, CDAI, scores ≤ 150) or adverse events.Data analysis : After assessing the validity of study design and independent, duplicate data extraction from selected trials, summary relative risks (RR) were calculated for each outcome. A test of heterogeneity was also calculated for each outcome using a random effects model.Results : Budesonide was more likely to induce remission than placebo (RR=1.82, 95% CI: 1.15–2.88) or 5-ASA (RR=1.73, 95% CI: 1.26–2.39), although only one trial compared budesonide to 5-ASA products. Although budesonide induced remission less frequently than conventional corticosteroids (RR=0.87, 95% CI: 0.76–0.995), there was no significant difference between conventional corticosteroids and budesonide for inducing remission among patients with a low disease activity (initial CDAI=200–300). Budesonide was significantly less likely to cause corticosteroid-associated adverse events than conventional corticosteroids (RR=0.65, 95% CI: 0.53–0.80). No significant difference in total adverse events or corticosteroid-associated adverse events was demonstrated between budesonide and 5-ASA or placebo.Conclusion : Budesonide is significantly more effective than placebo or 5-ASA for inducing remission of active Crohn's disease. Although budesonide is 13% less effective for the induction of remission in active Crohn's disease than conventional corticosteroids, it is less likely to cause corticosteroid-related adverse effects. Budesonide is ineffective in maintaining remission.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0044-2313
    Keywords: Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: LCAO MO Calculations on Donor-Acceptor Complexes. II. Formation of Donor-Acceptor Complexes of Cyclic Anhydrides with Lewis AcidsComplex formation between succinic or maleic anhydride with SbCl5, AlCl3, AlBr3 has been investigated by means of IR and PMR spectroscopy. In molar ratios of donor to acceptor 1:1 and 1:2 complex formation is uncomplete. A cleavage of anhydride bond system is not observed. Only one oxygen atom of anhydride is complexed with Lewis acid. From CNDO/2 calculation it is suggested that an unsymmetrical complex structure is most stable.
    Notes: Die Komplexbildung zwischen Bernsteinsäure- sowie Maleinsäureanhydrid mit SbCl5, AlCl3 und AlBr3 wird IR- und 1H-NMR-spektroskopisch untersucht. Für molare Donator-Akzeptor-Mischungen von 1:1 und 1:2 bleibt die Komplexbildung unvollständig. Eine Spaltung des Anhydrid-Bindungssystems wird nicht beobachtet. Nur ein Sauerstoffatom des Anhydridmoleküls wird von der Lewissäure koordiniert. Nach CNDO/2 Berechnungen ist eine unsymmetrische Komplexstruktur am stabilsten.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1912
    Keywords: Dog heart ; Beta-adrenoceptors ; Adenylate cyclase ; Heart ischemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We evaluated the effects of ischemic injury on the myocardial adenylate cyclase system, 5 h after ligation of the left anterior descending coronary in 5 anesthetized dogs. Crude cardiac membrane preparations were isolated from control and ischemic areas of ventricular myocardium and tested for: 1. L-(125I)iodocyanopindolol binding, in the absence and presence of ±-isoprenaline and GTP, and 2. adenylate cyclase activity. The density of beta-adrenoceptors increased by 35% in membranes from ischemic areas while the proportion of receptors in a high affinity state for ±-isoprenaline decreased from 43% to 20%. Adenylate cyclase activities in the basal state and under stimulation with NaF, forskolin, Gpp(NH)p, ±-isoprenaline and VIP were all markedly and similarly reduced, being only about 30% of comparable activities in membranes from control areas. The ±-isoprenaline subsensitivity of cardiac adenylate cyclase can, thus, be attributed to a defective enzymatic system and not to a reduction in the number of beta-adrenoceptors implying that the internal components of the system were more sensitive to acute ischemia than the outward oriented hormone receptors. It is tempting to ascribe this uncoupling to a functional depletion in the guanine nucleotide-binding regulatory protein Ns that might reflect a loss of high energy phosphate stores including GTP.
    Type of Medium: Electronic Resource
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