Are Tumor Marker Tests Applied Appropriately in Clinical Practice? A Healthcare Claims Data Analysis.

Tumor markers (TM) are crucial in the monitoring of cancer treatment. However, inappropriate requests for screening reasons have a high risk of false positive and negative findings, which can lead to patient anxiety and unnecessary follow-up examinations. We aimed to assess the appropriateness of TM testing in outpatient practice in Switzerland. We conducted a retrospective cohort study based on healthcare claims data. Patients who had received at least one out of seven TM tests (CEA, CA19-9, CA125, CA15-3, CA72-4, Calcitonin, or NSE) between 2018 and 2021 were analyzed. Appropriate determinations were defined as a request with a corresponding cancer-related diagnosis or intervention. Appropriateness of TM determination by patient characteristics and prescriber specialty was estimated by using multivariate analyses. A total of 51,395 TM determinations in 36,537 patients were included. An amount of 41.6% of all TM were determined appropriately. General practitioners most often determined TM (44.3%) and had the lowest number of appropriate requests (27.8%). A strong predictor for appropriate determinations were requests by medical oncologists. A remarkable proportion of TM testing was performed inappropriately, particularly in the primary care setting. Our results suggest that a considerable proportion of the population is at risk for various harms associated with misinterpretations of TM test results

Local adaptations to frost in marginal and central populations of the dominant forest tree Fagus sylvatica L. as affected by temperature and extreme drought in common garden experiments

Local adaptations to environmental conditions are of high ecological importance as they determine distribution ranges and likely affect species responses to climate change. Increased environmental stress (warming, extreme drought) due to climate change in combination with decreased genetic mixing due to isolation may lead to stronger local adaptations of geographically marginal than central populations. We experimentally observed local adaptations of three marginal and four central populations of Fagus sylvaticaL., the dominant native forest tree, to frost over winter and in spring (late frost). We determined frost hardiness of buds and roots by the relative electrolyte leakage in two common garden experiments. The experiment at the cold site included a continuous warming treatment; the experiment at the warm site included a preceding summer drought manipulation. In both experiments, we found evidence for local adaptation to frost, with stronger signs of local adaptation in marginal populations. Winter frost killed many of the potted individuals at the cold site, with higher survival in the warming treatment and in those populations originating from colder environments. However, we found no difference in winter frost tolerance of buds among populations, implying that bud survival was not the main cue for mortality. Bud late frost tolerance in April differed between populations at the warm site, mainly because of phenological differences in bud break. Increased spring frost tolerance of plants which had experienced drought stress in the preceding summer could also be explained by shifts in phenology. Stronger local adaptations to climate in geographically marginal than central populations imply the potential for adaptation to climate at range edges. In times of climate change, however, it needs to be tested whether locally adapted populations at range margins can successfully adapt further to changing conditions

Formation and abundance of 5-hydroxymethylcytosine in RNA.

RNA methylation is emerging as a regulatory RNA modification that could have important roles in the control and coordination of gene transcription and protein translation. Herein, we describe an in vivo isotope-tracing methodology to demonstrate that the ribonucleoside 5-methylcytidine (m(5)C) is subject to oxidative processing in mammals, forming 5-hydroxymethylcytidine (hm(5)C) and 5-formylcytidine (f(5)C). Furthermore, we have identified hm(5)C in total RNA from all three domains of life and in polyA-enriched RNA fractions from mammalian cells. This suggests m(5)C oxidation is a conserved process that could have critical regulatory functions inside cells.This work was supported by the Cambridge PhD Training Programme in Chemical Biology and Molecular Medicine and the Wellcome Trust (grant number 099232/Z/12/Z). Dr. Donna Bond is thanked for the provision of A. thaliana total RNA and Drs. Santiago Uribe-Lewis and Adele Murrell are acknowledged for the labelled mouse tissue supply.This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/cbic.201500013/abstract;jsessionid=61B9B3D8937FE50CFA4954A4C4B445B6.f02t04

Impact of vasopressin receptors on regulation of immune response in preeclampsia

Preeclampsia is a common disorder of pregnancy resulting in increased blood pressure and end organ effects. The pathogenesis of preeclampsia is multi-factorial. Arginine vasopressin (AVP) is increased in preeclampsia, and the chronic infusion of AVP throughout gestation has previously been shown to be sufficient to produce a phenotype of preeclampsia in C57BL/6J mice representative of some of the cardiovascular and renal events seen in humans. Alterations in T-helper cell populations and their effector cytokines are also known to occur in preeclampsia. Therefore, we proposed that the increased secretion of AVP may be responsible for the immune changes that occur in preeclampsia. We also hypothesized that known pharmacological AVP antagonist, vaptans, may be able to reverse the effects of AVP infusion

Endothelio-hematopoietic relationship: getting closer to the beginnings

The close association between hematopoietic and endothelial cells during embryonic development led to the proposal that they may originate from a common ancestor - the hemangioblast. Due to a lack of unique specific markers for in vivo cell fate tracking studies, evidence supporting this theory derives mainly from in vitro differentiation studies. Teixeira and colleagues describe a novel enhancer that drives specific eGFP expression in blood islands of the electroporated chick embryo, thereby presenting a tool potentially suitable for analysis of hemangioblast differentiation and development of blood islands

The Nucleoside Diphosphate Kinase Gene Nme3 Acts as Quantitative Trait Locus Promoting Non-Mendelian Inheritance

The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (>95%) from heterozygous (t/+) males to their offspring. This phenotype is termed transmission ratio distortion (TRD) and is caused by the interaction of the t-complex responder (Tcr) with several quantitative trait loci (QTL), the t-complex distorters (Tcd1 to Tcd4), all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas +-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter-balanced by the responder, SMOKTcr, a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa

Sensitive Spectroscopic Detection of Large and Denatured Protein Aggregates in Solution by Use of the Fluorescent Dye Nile Red

The fluorescent dye Nile red was used as a probe for the sensitive detection of large, denatured aggregates of the model protein β-galactosidase (E. coli) in solution. Aggregates were formed by irreversible heat denaturation of β-galactosidase below and above the protein’s unfolding temperature of 57.4°C, and the presence of aggregates in heated solutions was confirmed by static light scattering. Interaction of Nile red with β-galactosidase aggregates led to a shift of the emission maximum (λmax) from 660 to 611 nm, and to an increase of fluorescence intensity. Time-resolved fluorescence and fluorescence correlation spectroscopy (FCS) measurements showed that Nile red detected large aggregates with hydrodynamic radii around 130 nm. By steady-state fluorescence measurements, it was possible to detect 1 nM of denatured and aggregated β-galactosidase in solution. The comparison with size exclusion chromatography (SEC) showed that native β-galactosidase and small aggregates thereof had no substantial effect on the fluorescence of Nile red. Large aggregates were not detected by SEC, because they were excluded from the column. The results with β-galactosidase demonstrate the potential of Nile red for developing complementary analytical methods that overcome the size limitations of SEC, and can detect the formation of large protein aggregates at early stages

Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling

Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment