Clinical relevance and utility of cetuximab-related changes in magnesium and calcium serum levels

Hypomagnesemia and hypocalcemia are common adverse events during cetuximab treatment. The influence of the chemotherapeutic combination on serum levels is unknown and the predictive value is currently under discussion. This analysis investigated 79 patients who had received cetuximab for at least 6 weeks in the day clinic of the Comprehensive Cancer Center, University of Munich. Calcium and magnesium serum levels were analyzed weekly; tumor response and adverse events were followed. Thirty-eight patients had metastatic colorectal cancer (mCRC) and the predictive value of hypomagnesemia was tested in these patients. During therapy, calcium serum levels decreased to about 97% of the baseline levels and were maintained for the duration of treatment. Magnesium levels showed a significant time-dependent decrease. Serum levels of magnesium were lower when cetuximab was combined with a platinum derivative. After a treatment duration of 12 weeks, magnesium levels decreased to 70% in platinum-treated patients, whereas they decreased to only 90% of baseline in patients who did not receive platinum therapy. In patients treated for mCRC, a decrease of serum magnesium below 95% of the baseline levels 14 days after initiating treatment separated patients significantly in terms of survival times. Magnesium levels decrease in a time-dependent manner during cetuximab therapy. As hypomagnesemia was more prominent in patients receiving platinum agents, magnesium measurements may be advised in these patients. In mCRC patients treated with cetuximab, day-14 magnesium serum levels correlated with treatment efficacy

Communications Biophysics

Contains reports on four research projects.National Institutes of Health (Grant 5 P01 NS13126-02)National Institutes of Health (Grant 5 K04 NS00113-03)National Institutes of Health (Grant 2 ROI NS11153-02A1)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 RO1 NS10916-03)National Institutes of Health (Fellowship 1 F32 NS05327)National Institutes of Health (Grant 5 ROI NS12846-02)National Institutes of Health (Fellowship 1 F32 NS05266)Edith E. Sturgis FoundationNational Institutes of Health (Grant 1 R01 NS11680-01)National Institutes of Health (Grant 2 RO1 NS11080-04)National Institutes of Health (Grant 5 T32 GIM107301-03)National Institutes of Health (Grant 5 TOI GM01555-10

Communications Biophysics

Contains research objectives and summary of research on nine research projects split into four sections.National Institutes of Health (Grant 5 ROI NS11000-03)National Institutes of Health (Grant 1 P01 NS13126-01)National Institutes of Health (Grant 1 RO1 NS11153-01)National Institutes of Health (Grant 2 R01 NS10916-02)Harvard-M.I.T. Rehabilitation Engineering CenterU. S. Department of Health, Education, and Welfare (Grant 23-P-55854)National Institutes of Health (Grant 1 ROl NS11680-01)National Institutes of Health (Grant 5 ROI NS11080-03)M.I.T. Health Sciences Fund (Grant 76-07)National Institutes of Health (Grant 5 T32 GM07301-02)National Institutes of Health (Grant 5 TO1 GM01555-10

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 5 KO4 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Training Grant 1 T32 NS07099)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROI NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Edith E. Sturgis FoundationHealth Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Fellowship 5 F32 NS05327)National Institutes of Health (Grant 2 ROI NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium

AbstractObservational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P &lt; 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P &lt; 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.</jats:p

Enjoy! Assertive Language and Consumer Compliance in (Non)Hedonic Contexts

This paper is concerned with the tension between consumer persuasion and freedom of choice. We study how assertive language (as in the slogan Just do it!) affects consumer compliance in hedonic vs. utilitarian contexts. Previous literature consistently claimed that forceful language would cause reactance and decreased compliance. However, we find in four studies that assertive persuasion is effective in contexts involving hedonic goods and hedonically framed utilitarian goods. Our hypotheses emerge from sociolinguistic research and confirm the relevance of linguistic research in consumer behavior

Recurrent seasonal outbreak of an emerging serotype of Shiga toxin-producing Escherichia coli (STEC O55:H7 Stx2a) in the south west of England, July 2014 to September 2015.

The first documented British outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 began in the county of Dorset, England, in July 2014. Since then, there have been a total of 31 cases of which 13 presented with haemolytic uraemic syndrome (HUS). The outbreak strain had Shiga toxin (Stx) subtype 2a associated with an elevated risk of HUS. This strain had not previously been isolated from humans or animals in England. The only epidemiological link was living in or having close links to two areas in Dorset. Extensive investigations included testing of animals and household pets. Control measures included extended screening, iterative interviewing and exclusion of cases and high risk contacts. Whole genome sequencing (WGS) confirmed that all the cases were infected with similar strains. A specific source could not be identified. The combination of epidemiological investigation and WGS indicated, however, that this outbreak was possibly caused by recurrent introductions from a local endemic zoonotic source, that a highly similar endemic reservoir appears to exist in the Republic of Ireland but has not been identified elsewhere, and that a subset of cases was associated with human-to-human transmission in a nursery

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

AbstractMany individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.</jats:p