Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification

The dynamics of short- and long-term CDS-spreads of banks

This paper studies 'Stylised Facts' and 'Determinants' of short-and long-term CDS-spreads of banks. As short-term spreads we choose 6M-, as long-term spreads we choose 5Y-spreads. In the section 'Stylised Facts' we found that the correlation between short-and long-term spreads for the total period is high (97%). However, the correlation in sub-periods varies across all possible correlations. Particularly, spreads can have negative correlation. In contrast to [Covitz and Downing, 2007], we find high positive (Covitz/Downing: high negative) correlation for turbulent market circumstances. In the section 'Deteminants' we confirm the Merton-factors (stock price, stock price volatility, interest rate level) for the 5Y-segment, but not for the 6M-segment. Furthermore, we do not find any empirical support that short-term spreads are particularly sensitive to illiquidity factors. In that sense, we also contrast [Covitz and Downing, 2007]. --Liquidity,insolvency,banks

Studies on the Regulation of Mu Opioid Receptor mRNA Expression in SHSY-5Y Human Neuroblastoma Cells

Prolonged exposure to morphine down-regulates mu opioid receptors (MOR) on both undifferentiated and differentiated (retinoic acid or phorbol ester treated) SHSY-5Y cells. However, morphine pretreatment does not alter MOR receptor affinity for morphine. To investigate the molecular basis for MOR regulation after exposure to its selective agonists, we have developed a quantitative competitive reverse transcriptase-polymerase chain reaction (QC-RT PCR) to quantify the expression of MOR in SHSY-SY cells. Differentiation of SHSY-5Y cells with retinoic acid or phorbol ester up regulated MOR mRNA expression by 30 % and 78%, respectively. A 24 hours treatment with morphine (10 µM) down regulated MOR mRNA, an effect that was partially reversed by naloxone. However, after exposure to endomorphin-1, 2 for 24 hours, MOR mRNA expression is significantly increased in the differentiated and non-differentiated SHSY-5Y cells. Differences in intracellular cAMP accumulation are also observed in the differentiated and non-differentiated SHSY-5Y cells after the chronic exposure to morphine and endomorphin-1,-2. Taken together, a significant component of SHSY-5Y cellular adaptation during chronic morphine treatment may occur at the mRNA level and our data suggest different morphine or endomorphin-1, -2 mediated molecular events in the MOR receptor regulation

On the simplest sextic fields and related Thue equations

We consider the parametric family of sextic Thue equations $$x^6-2mx^5y-5(m+3)x^4y^2-20x^3y^3+5mx^2y^4+2(m+3)xy^5+y^6=\lambda$$ where $m\in\mathbb{Z}$ is an integer and $\lambda$ is a divisor of $27(m^2+3m+9)$. We show that the only solutions to the equations are the trivial ones with $xy(x+y)(x-y)(x+2y)(2x+y)=0$.Comment: 12 pages, 2 table

Accuracy of prediction models for long-term type 2 diabetes remission after gastric bypass

AimTo evaluate the accuracy of DiaBetter, DiaRem, Ad-DiaRem and 5y-Ad-DiaRem scores' at predicting T2D remission 10 or more years after surgery.MethodsPatients with obesity and T2D (n = 126) submitted to RYGB with 10 or more years of follow-up. It was a unicentric trial. Pre-operative anthropometric and clinical data was retrieved to calculate DiaRem, DiaBetter, Ad-DiaRem and 5y-Ad-DiaRem scores, while a hospital visit was conducted to assess current diabetes status. The area under the receiver operating characteristic (AUROC) curve was calculated as estimate of the scores' accuracy to predict long-term T2D remission.ResultsAmong the entire cohort (n = 126), 70 subjects (55.6%) achieved and maintained T2D remission 10 or more years after RYGB. The 5y-Ad-DiaRem score was the one that depicted the highest discriminative power (AUROC = 0.838) to predict long-term T2D remission when compared to DiaBetter (AUROC = 0.735), DiaRem (AUROC = 0.721) and Ad-DiaRem (AUROC = 0.720).ConclusionThe score with highest accuracy to predict long-term T2D remission after RYGB surgery was the 5y-Ad-DiaRem. Yet, the available scores accuracy to predict T2D remission in the long term is still suboptimal, highlighting the unmet need for a better scoring system

DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life

DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p ≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.</p

Forecasting exchange rates of major currencies with long maturity forward rates. Bruegel Working Paper | Issue 02 April 2020. Plus Annex in separate pdf

This paper presents unprecedented exchange rate forecasting results, based upon a new model that approximates the gap between the fundamental equilibrium exchange rate and the actual exchange rate with the longmaturity forward exchange rate. The theoretical derivation of our forecasting equation is consistent with the monetary model of exchange rates. Our model outperforms the random walk in out-of-sample forecasting of twelve major currency pairs over the short and long horizon forecasts for the 1990- 2020 period. The results are robust for all sub-periods, with the exception of the years around the collapse of Lehman Brothers in September 2008. Our results are robust to alternative model specifications, single equation and panel estimation, recursive and rolling estimation, and alternate data construction methods. The model performs better when the long-maturity forward exchange rate is assumed to be stationary, as opposed to assuming non-stationarity. The improvement in forecast accuracy from our model is economically and statistically significant for almost all exchange-rate series. The model is simple, linear, easy to replicate, and the data we use is available in real time and not subject to revision