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

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

Mode of action uncovered for the specific reduction of methane emissions from ruminants by the small molecule 3-nitrooxypropanol

Ruminants, such as cows, sheep, and goats, predominantly ferment in their rumen plant material to acetate, propionate, butyrate, CO, and methane. Whereas the short fatty acids are absorbed and metabolized by the animals, the greenhouse gas methane escapes via eructation and breathing of the animals into the atmosphere. Along with the methane, up to 12% of the gross energy content of the feedstock is lost. Therefore, our recent report has raised interest in 3-nitrooxypropanol (3-NOP), which when added to the feed of ruminants in milligram amounts persistently reduces enteric methane emissions from livestock without apparent negative side effects [Hristov AN, et al. (2015) Proc Natl Acad Sci USA 112(34):10663-10668]. We now show with the aid of in silico, in vitro, and in vivo experiments that 3-NOP specifically targets methyl-coenzyme M reductase (MCR). The nickel enzyme, which is only active when its Ni ion is in the+1 oxidation state, catalyzes the methane-forming step in the rumen fermentation. Molecular docking suggested that 3-NOP preferably binds into the active site of MCR in a pose that places its reducible nitrate group in electron transfer distance to Ni(I). With purified MCR, we found that 3-NOP indeed inactivates MCR at micromolar concentrations by oxidation of its active site Ni(I). Concomitantly, the nitrate ester is reduced to nitrite, which also inactivates MCR at micromolar concentrations by oxidation of Ni(I). Using pure cultures, 3-NOP is demonstrated to inhibit growth of methanogenic archaea at concentrations that do not affect the growth of nonmethanogenic bacteria in the rumen.We thank Peter Livant (Auburn University), Elisabeth Jimenez (Consejo Superior de Investigaciones Cientificas), John Wallace (University of Aberdeen), and Jamie Newbold (Aberystwyth University) for the use of the gas chromatograph, for the in vitro culture work, and for providing stock pure cultures, respectively; Ulrich Ermler and the staff of the PXII beam line at Swiss Light Source (Villigen, Switzerland) for helping with the X-ray data collection; and David Rinaldo (Schrödinger, LLC) for molecular modeling support.Peer Reviewe

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

Don't Make Me Angry! A Psychophysiological Examination of the Anger–Performance Relationship in Intermediate and Elite Fencers

We aimed to identify the effect of state-anger on precision, speed, and power components of performance during fencing attacks. We conducted a laboratory-based, single-case research experiment to test the fine motor task performance of two experienced and two elite-level fencers under two emotional states: anger and emotion-neutral. We assessed anger via psychophysiological and self-report measures, and we induced anger via a brief imagery intervention. Through the use of an innovative design, which included multiple measures of change, we showed that anger had a consistent negative effect on precision but an inconsistent relationship with response time and muscle activity. The current research design and protocol offer a novel and in-depth method for examining the specific relationships between affective states, emotions, and the complexities that underpin performance. The specific effects of anger on performance were multifarious, complex, and inconsistent. Nonetheless, the results tend to indicate that anger facilitates reaction time and debilitates performance, and these effects were clearer for the most elite performers. The effects of anger on performance are clearly complex, so it would be rather premature to make any suggestions for future practice at this point. Nonetheless, the clearer findings with the elite fencers indicate that researchers will likely yield the most fruitful insights by examining the effects of emotion of performance in elite performers

A higher-resolution version of the Max Planck Institute Earth System Model (MPI-ESM1.2-HR)

The MPI‐ESM1.2 is the latest version of the Max Planck Institute Earth System Model and is the baseline for the Coupled Model Intercomparison Project Phase 6 and current seasonal and decadal climate predictions. This paper evaluates a coupled higher‐resolution version (MPI‐ESM1.2‐HR) in comparison with its lower‐resolved version (MPI‐ESM1.2‐LR). We focus on basic oceanic and atmospheric mean states and selected modes of variability, the El Niño/Southern Oscillation and the North Atlantic Oscillation. The increase in atmospheric resolution in MPI‐ESM1.2‐HR reduces the biases of upper‐level zonal wind and atmospheric jet stream position in the northern extratropics. This results in a decrease of the storm track bias over the northern North Atlantic, for both winter and summer season. The blocking frequency over the European region is improved in summer, and North Atlantic Oscillation and related storm track variations improve in winter. Stable Atlantic meridional overturning circulations are found with magnitudes of ~16 Sv for MPI‐ESM1.2‐HR and ~20 Sv for MPI‐ESM1.2‐LR at 26°N. A strong sea surface temperature bias of ~5°C along with a too zonal North Atlantic current is present in both versions. The sea surface temperature bias in the eastern tropical Atlantic is reduced by ~1°C due to higher‐resolved orography in MPI‐ESM‐HR, and the region of the cold‐tongue bias is reduced in the tropical Pacific. MPI‐ESM1.2‐HR has a well‐balanced radiation budget and its climate sensitivity is explicitly tuned to 3 K. Although the obtained reductions in long‐standing biases are modest, the improvements in atmospheric dynamics make this model well suited for prediction and impact studies

Children's trust and the development of prosocial behavior

This study examined the role of children’s trust beliefs and trustworthiness in the development of prosocial behavior using data from four waves of a longitudinal study in a large, ethnically diverse sample of children in Switzerland (mean age = 8.11 years at Time 1, N = 1,028). Prosocial behavior directed towards peers was measured at all assessment points by teacher reports. Children’s trust beliefs and their trustworthiness with peers were assessed and calculated by a social relations analysis at the first assessment point using children’s reports of the extent to which classmates kept promises. In addition, teacher reports of children’s trustworthiness were assessed at all four assessment points. Latent growth curve modeling yielded a decrease in prosocial behavior over time. Peer- and teacher-reported trustworthiness predicted higher initial levels of prosocial behavior, and peer-reported trustworthiness predicted less steep decreases in prosocial behavior over time. Autoregressive cross-lagged analysis also revealed bidirectional longitudinal associations between teacher-reported trustworthiness and prosocial behavior. We discuss the implications of the findings for research on the role of trust in the development of children’s prosocial behavior

Imaging Mass Spectrometry: Hype or Hope?

Imaging mass spectrometry is currently receiving a significant amount of attention in the mass spectrometric community. It offers the potential of direct examination of biomolecular patterns from cells and tissue. This makes it a seemingly ideal tool for biomedical diagnostics and molecular histology. It is able to generate beautiful molecular images from a large variety of surfaces, ranging from cancer tissue sections to polished cross sections from old-master paintings. What are the parameters that define and control the implications, challenges, opportunities, and (im)possibilities associated with the application of imaging MS to biomedical tissue studies. Is this just another technological hype or does it really offer the hope to gain new insights in molecular processes in living tissue? In this critical insight this question is addressed through the discussion of a number of aspects of MS imaging technology and sample preparation that strongly determine the outcome of imaging MS experiments

Variation in genes encoding eosinophil granule proteins in atopic dermatitis patients from Germany

<p>Abstract</p> <p>Background</p> <p>Atopic dermatitis (AD) is believed to result from complex interactions between genetic and environmental factors. A main feature of AD as well as other allergic disorders is serum and tissue eosinophilia. Human eosinophils contain high amounts of cationic granule proteins, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), eosinophil peroxidase (EPO) and major basic protein (MBP). Recently, variation in genes encoding eosinophil granule proteins has been suggested to play a role in the pathogenesis of allergic disorders. We therefore genotyped selected single nucleotide polymorphisms within the <it>ECP, EDN, EPO </it>and <it>MBP </it>genes in a cohort of 361 German AD patients and 325 healthy controls.</p> <p>Results</p> <p>Genotype and allele frequencies did not differ between patients and controls for all polymorphisms investigated in this study. Haplotype analysis did not reveal any additional information.</p> <p>Conclusion</p> <p>We did not find evidence to support an influence of variation in genes encoding eosinophil granule proteins for AD pathogenesis in this German cohort.</p