Are serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin?

Background: Serial kinetics of serum CA 19-9 levels have been reported to reflect response and survival in patients with pancreatic cancer undergoing surgery, radiotherapy, and chemotherapy. We prospectively studied serial kinetics of serum CA 19-9 levels of patients with locally advanced or metastatic disease treated with gemcitabine and cisplatin. Patients and Methods: Enrolled in the study were 87 patients (female/male = 26/61; stage III/IV disease = 24/63). Patients received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 50 mg/m(2) on days 1 and 15, every 4 weeks. Serum samples were collected at the onset of chemotherapy and before the start of a new treatment cycle (day 28). Results: 77 of 87 patients (88.5%) with initially elevated CA 19-9 levels were included for evaluation. According to imaging criteria, 4 (5.2%) achieved a complete remission and 11 (14.3%) achieved partial remission, yielding an overall response rate of 19.5%. 43 (55.8%) patients were CA 19-9 responders, defined by greater than or equal to50% decrease in CA 19-9 serum levels within 2 months after treatment initiation. Except for one, all patients who had responded by imaging criteria (n = 14) fulfilled the criterion of a CA 19-9 responder. Despite being characterized as non-responders by CT-imaging criteria (stable/progressive disease), 29 patients were classified as CA 19-9 responders (positive predictive value 32.5%). Independent of the response evaluation by CT, CA 19-9 responders survived significantly longer than CA 19-9 non-responders (295 d; 95% CI: 285-445 vs. 174 d; 95% CI: 134-198; p = 0.022). Conclusion: CA 19-9 kinetics in serum serve as an early and reliable indicator of response and help to predict survival in patients with advanced pancreatic cancer receiving effective treatment with gemcitabine and cisplatin

Large-Scale Production of Bioactive Ingredients as Supplements for Healthy Human and Animal Nutrition

In this review, synthetic strategies and the development of environmentally benign methods for the production of economically important vitamins, carotenoids, and nutraceuticals used as food and feed supplements are illustrated by selected examples. The application of efficient catalytic transformations in multi-step chemical syntheses of such natural products enables technically feasible and cost-effective processes. For the preparation of fat-soluble (isoprenoid) vitamins A and E and the water-soluble vitamin (+)-biotin, homogeneous metal catalysis, including enantioselective transformations, heterogeneous and enzymatic catalysis serve as key methodologies. In the area of carotenoids, general building concepts and coupling methods for the total synthesis of ?-carotene and astaxanthin are discussed. Biotechnological methods and isolation from natural sources are also employed successfully, as exemplified for the xanthophyll lutein and the antioxidant (–)-epigallocatechin gallate. Lastly, key steps of the chemical synthesis of the polyphenol resveratrol are highlighted

Arginine methylation of yeast mRNA-binding protein Npl3 directly affects its function, nuclear export, and intranuclear protein interactions

Arginine methylation can affect both nucleocytoplasmic transport and protein-protein interactions of RNA-binding proteins. These effects are seen in cells that lack the yeast hnRNP methyltransferase (HMT1), raising the question of whether effects on specific proteins are direct or indirect. The presence of multiple arginines in individual methylated proteins also raises the question of whether overall methylation or methylation of a subset of arginines affects protein function. We have used the yeast mRNA-binding protein Npl3 to address these questions in vivo. Matrix-assisted laser desorption/ionization Fourier transform mass spectrometry was used to identify 17 methylated arginines in Npl3 purified from yeast: whereas 10 Arg-Gly-Gly (RGG) tripeptides were exclusively dimethylated, variable levels off methylation were found for 5 RGG and 2 RG motif arginines. We constructed a set of Npl3 proteins in which subsets of the RGG arginines were mutated to lysine. Expression of these mutant proteins as the sole form of Npl3 specifically affected growth of a strain that requires Hmtl. Although decreased growth generally correlated with increased numbers of Arg-to-Lys mutations, lysine substitutions in the N terminus of the RGG domain showed more severe effects. Npl3 with all 15 RGG arginines mutated to lysine exited the nucleus independent of Hmtl, indicating a direct effect of methylation on Npl3 transport. These mutations also resulted in a decreased, methylation-independent interaction of Npl3 with transcription elongation factor Tho2 and inhibited Npl3 self-association. These results support a model in which arginine methylation facilitates Npl3 export directly by weakening contacts with nuclear proteins. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc

Anthracycline-Induced Cardiotoxicity: Cardiac Monitoring by Continuous Wave-Doppler Ultrasound Cardiac Output Monitoring and Correlation to Echocardiography

Background: Anthracyclines are agents with a well-known cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using real-time continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers. Methods: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4). Results: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (Delta T0-T4, T0 71 +/- 7.8%, T4 69.5 +/- 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (Delta T0-T4, T0 54 +/- 19.2 ml, T4 50.5 +/- 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated. Conclusions: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography

Markov analysis of stochastic resonance in a periodically driven integrate-fire neuron

We model the dynamics of the leaky integrate-fire neuron under periodic stimulation as a Markov process with respect to the stimulus phase. This avoids the unrealistic assumption of a stimulus reset after each spike made in earlier work and thus solves the long-standing reset problem. The neuron exhibits stochastic resonance, both with respect to input noise intensity and stimulus frequency. The latter resonance arises by matching the stimulus frequency to the refractory time of the neuron. The Markov approach can be generalized to other periodically driven stochastic processes containing a reset mechanism.Comment: 23 pages, 10 figure

Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease

BACKGROUND: For allergic disorders, the increasing prevalence over the past decade has been attributed in part to the lack of microbial burden in developed countries ('hygiene hypothesis'). Variation in genes encoding toll-like receptors (TLRs) as the receptor system for the first innate immune response to microbial stimuli has been implicated in various inflammatory diseases. We evaluated here the role of a coding variation, Ser249Pro, in the TLR6 gene in the pathogenesis of asthma, atopic dermatitis (AD) and chronic obstructive pulmonary disease (COPD). METHODS: Genotyping of the Ser249Pro polymorphism in 68 unrelated adult patients and 132 unrelated children with asthma, 185 unrelated patients with COPD, 295 unrelated individuals with AD and 212 healthy control subjects was performed by restriction enzyme digestion. RESULTS: We found a weak association of the 249Ser allele with childhood asthma (p = 0.03). Yet, significance was lost after Bonferroni correction. No association was evident for AD or COPD. CONCLUSION: Variation in TLR6 might play a role in the pathogenesis of childhood asthma