Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability

<p>Abstract</p> <p>Background</p> <p>Protein tyrosine phosphatases (PTPs) like their antagonizing protein tyrosine kinases are key regulators of signal transduction thereby assuring normal control of cellular growth and differentiation. Increasing evidence suggests that mutations in PTP genes are associated with human malignancies. For example, mutational analysis of the tyrosine phosphatase (PTP) gene superfamily uncovered genetic alterations in about 26% of colorectal tumors. Since in these studies tumors have not been stratified according to genetic instability status we hypothesized that colorectal tumors characterized by high-level of microsatellite instability (MSI-H) might show an increased frequency of frameshift mutations in those PTP genes that harbor long mononucleotide repeats in their coding region (cMNR).</p> <p>Results</p> <p>Using bioinformatic analysis we identified 16 PTP candidate genes with long cMNRs that were examined for genetic alterations in 19 MSI-H colon cell lines, 54 MSI-H colorectal cancers, and 17 MSI-H colorectal adenomas. Frameshift mutations were identified only in 6 PTP genes, of which PTPN21 show the highest mutation frequency at all in MSI-H tumors (17%).</p> <p>Conclusion</p> <p>Although about 32% of MSI-H tumors showed at least one affected PTP gene, and cMNR mutation rates in PTPN21, PTPRS, and PTPN5 are higher than the mean mutation frequency of MNRs of the same length, mutations within PTP genes do not seem to play a common role in MSI tumorigenesis, since no cMNR mutation frequency reached statistical significance and therefore, failed prediction as a Positive Selective Target Gene.</p

Remission, continuation and incidence of eating disorders during early pregnancy: a validation study in a population-based birth cohort

Background—The objective of this study was to validate previously published rates of remission, continuation, and incidence of broadly defined eating disorders during pregnancy. The previous rate modeling was done by our group (Bulik et al. 2007) and yielded participants halfway into recruitment of the planned 100,000 pregnancies in the Norwegian Mother and Child (MoBa) Cohort at the Norwegian Institute of Public Health. This study aimed to internally validate the findings with the completed cohort. Methods—77267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were included. Participants were split into a “training” sample (n=41243) based on participants in the MoBa version 2 dataset of the original study and a “validation” sample (n=36024) comprising individuals in the MoBa version 5 dataset that were not in the original study (Bulik et al. 2007). Internal validation of all original rate models involved fitting a calibration model to compare model parameters between the “training” and “validation” samples as well as bootstrap estimates of bias in the entire version 5 dataset. Results—Remission, continuation, and incidence estimates from the “training” sample remained stable when evaluated via a split sample validation procedure. Pre-pregnancy prevalence estimates in the “validation” sample were 0.1% for anorexia nervosa, 1.0% for bulimia nervosa (BN), 3.3% for binge eating disorder (BED), and 0.1% for purging disorder (EDNOS-P). In early pregnancy, estimates were 0.2% for BN, 4.8% for BED, and <0.01% for EDNOS-P. Consistent with the original study, incident BN and EDNOS-P during pregnancy were rare. For BED, the adjusted incidence rate in the “validation” sample was 1.17 per 1000 person-weeks. The highest rates were for full or partial remission for BN and EDNOS-P, and continuation for BED. Conclusions—This study provides evidence of validity of previously estimated rates of remission, continuation, and incidence of eating disorders during pregnancy. Eating disorders during pregnancy were relatively common, occurring in nearly 1 in every 20 women, although almost all were cases of BED. Pregnancy was a window of remission from BN but a window of vulnerability for onset and continuation of BED. Training to detect the signs and symptoms of eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention

Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: possible mode of function

Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide

Diet matters, particularly in pregnancy – Results from MoBa studies of maternal diet and pregnancy outcomes

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Awareness that maternal diet may influence the outcome of pregnancy as well as the long-term health of mother and child has increased in recent years. A new food frequency questionnaire (FFQ) was developed and validated specifically for the Norwegian Mother and Child Cohort Study (MoBa). The MoBa FFQ is a semi-quantitative tool which covers the average intake of food, beverages and dietary supplements during the first 4 to 5 months of pregnancy. It includes questions about intakes of 255 foods and dishes and was used from 2002 onwards. Data assessed by the MoBa FFQ is available for 87,700 pregnancies. Numerous sub-studies have examined associations between dietary factors and health outcomes in MoBa. The aim of this paper is to summarize the results from 19 studies of maternal diet and pregnancy outcomes, which is the complete collection of studies based on the MoBa FFQ and published before September 2014. The overall research question is whether maternal diet – from single substances to dietary patterns – matters for pregnancy outcome. The pregnancy outcomes studied till now include birth size measures, infants being small and large for gestational age, pregnancy duration, preterm delivery, preeclampsia, as well as maternal gestational weight gain and postpartum weight retention. As a whole, the results from these studies corroborate that the current dietary recommendations to pregnant women are sound and that maternal diet during pregnancy is likely to contribute to reduce the risk of pregnancy complications including preterm birth, preeclampsia, and reduced foetal growth. The results provide supporting evidence for recommending pregnant women to consume vegetables, fruit, whole grain, fish, dairy, and water regularly and lower the intake of sugar sweetened beverages, processed meat products and salty snacks. The results showing negative impact of even low levels of environmental contaminants support the precautionary advice on consumption of foods containing these. New findings are that particularly lean fish explained the positive association between seafood intake and foetal growth, and the indications of a protective effect of probiotic and antimicrobial foods on pregnancy outcomes. This points to the importance of diet composition for a healthy gut flora and the body’s immune response. Although these studies are observational and cannot infer causality, the results identify diet as an important modifiable lifestyle factor, suggesting that healthy eating, defined as following the official recommendations, is particularly important in pregnanc

SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology

About 15% of human colorectal cancers and, at varying degrees, other tumor entities as well as nearly all tumors related to Lynch syndrome are hallmarked by microsatellite instability (MSI) as a result of a defective mismatch repair system. The functional impact of resulting mutations depends on their genomic localization. Alterations within coding mononucleotide repeat tracts (MNRs) can lead to protein truncation and formation of neopeptides, whereas alterations within untranslated MNRs can alter transcription level or transcript stability. These mutations may provide selective advantage or disadvantage to affected cells. They may further concern the biology of microsatellite unstable cells, e.g. by generating immunogenic peptides induced by frameshifts mutations. The Selective Targets database (http://www.seltarbase.org) is a curated database of a growing number of public MNR mutation data in microsatellite unstable human tumors. Regression calculations for various MSI–H tumor entities indicating statistically deviant mutation frequencies predict TGFBR2, BAX, ACVR2A and others that are shown or highly suspected to be involved in MSI tumorigenesis. Many useful tools for further analyzing genomic DNA, derived wild-type and mutated cDNAs and peptides are integrated. A comprehensive database of all human coding, untranslated, non-coding RNA- and intronic MNRs (MNR_ensembl) is also included. Herewith, SelTarbase presents as a plenty instrument for MSI-carcinogenesis-related research, diagnostics and therapy

The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect

BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition

Validity of mobile electronic data capture in clinical studies: a pilot study in a pediatric population.

BACKGROUND: Clinical studies in children are necessary yet conducting multiple visits at study centers remains challenging. The success of "care-at-home" initiatives and remote clinical trials suggests their potential to facilitate conduct of pediatric studies. This pilot aimed to study the feasibility of remotely collecting valid (i.e. complete and correct) saliva samples and clinical data utilizing mobile technology. METHODS: Single-center, prospective pilot study in children undergoing elective tonsillectomy at the University of Basel Children's Hospital. Data on pain scores and concomitant medication and saliva samples were collected by caregivers on two to four inpatient study days and on three consecutive study days at home. A tailored mobile application developed for this study supported data collection. The primary endpoint was the proportion of complete and correct caregiver-collected data (pain scale) and saliva samples in the at-home setting. Secondary endpoints included the proportion of complete and correct saliva samples in the inpatient setting, subjective feasibility for caregivers, and study cost. RESULTS: A total number of 23 children were included in the study of which 17 children, median age 6.0 years (IQR 5.0, 7.4), completed the study. During the at-home phase, 71.9% [CI = 64.4, 78.6] of all caregiver-collected pain assessments and 53.9% [CI = 44.2, 63.4] of all saliva samples were complete and correct. Overall, 64.7% [CI = 58.7, 70.4] of all data collected by caregivers at home was complete and correct. The predominant reason for incorrectness of data was adherence to the timing of predefined patient actions. Participating caregivers reported high levels of satisfaction and willingness to participate in similar trials in the future. Study costs for a potential sample size of 100 patients were calculated to be 20% lower for the at-home than for a traditional in-patient study setting. CONCLUSIONS: Mobile device supported studies conducted at home may provide a cost-effective approach to facilitate conduct of clinical studies in children. Given findings in this pilot study, data collection at home may focus on electronic data capture rather than biological sampling

Dimethylarginine Dimethylaminohydrolase-1 Transgenic Mice Are Not Protected from Ischemic Stroke

Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in humans. It is eliminated primarily by enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH).We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice. Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, ADMA plasma concentrations were significantly decreased, cerebral hDDAH expression and protein significantly increased in transgenic animals. Interestingly, neither brain tissue DDAH activity nor ADMA concentrations were different between TG and WT mice. In contrast, muscular DDAH activity was generally lower than in brain but significantly increased in TG mice.Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is due to high basal cerebral DDAH activity, which is not further increasable by transgenic overexpression of DDAH

Perturbation theory for quantum-mechanical observables

The quantum-mechanical state vector is not directly observable even though it is the fundamental variable that appears in Schrodinger's equation. In conventional time-dependent perturbation theory, the state vector must be calculated before the experimentally-observable expectation values of relevant operators can be computed. We discuss an alternative form of time-dependent perturbation theory in which the observable expectation values are calculated directly and expressed in the form of nested commutators. This result is consistent with the fact that the commutation relations determine the properties of a quantum system, while the commutators often have a form that simplifies the calculation and avoids canceling terms. The usefulness of this method is illustrated using several problems of interest in quantum optics and quantum information processing.Comment: Submitted to Phys. Rev. A. 17 pages, 4 figures. Minor change