Educational attainment polygenic scores,socioeconomic factors,and cortical structure in children and adolescents

Genome‐wide polygenic scores for educational attainment (PGS‐EA) and socioeconomic factors, which are correlated with each other, have been consistently associated with academic achievement and general cognitive ability in children and adolescents. Yet, the independent associations of PGS‐EA and socioeconomic factors with specific underlying factors at the neural and neurocognitive levels are not well understood. The main goals of this study were to examine the unique contributions of PGS‐EA and parental education to cortical structure and neurocognitive skills in children and adolescents, and the associations among PGS‐EA, cortical structure, and neurocognitive skills. Participants were typically developing 3‐ to 21‐year‐olds (53% male; N = 391). High‐resolution, T1‐weighted magnetic resonance imaging data were acquired, and cortical thickness (CT) and surface area (SA) were measured. PGS‐EA were computed based on the EA3 genome‐wide association study of educational attainment. Participants completed executive function, vocabulary, and episodic memory tasks. Higher PGS‐EA and parental education were independently and significantly associated with greater total SA and vocabulary. Higher PGS‐EA was significantly associated with greater SA in the left medial orbitofrontal gyrus and inferior frontal gyrus, which was associated with higher executive function. Higher parental education was significantly associated with greater SA in the left parahippocampal gyrus after accounting for PGS‐EA and total brain volume. These findings suggest that education‐linked genetics may influence SA in frontal regions, leading to variability in executive function. Associations of parental education with cortical structure in children and adolescents remained significant after controlling for PGS‐EA, a source of genetic confounding.     

Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.     

Impact of Fruit and Vegetable Protein vs. Milk Protein on Metabolic Control of Children with Phenylketonuria: A Randomized Crossover Controlled Trial

Fruits and vegetables containing phenylalanine ≤ 75 mg/100 g (except potatoes) have little impact on blood phenylalanine in phenylketonuria (PKU). In a randomized, controlled, crossover intervention trial, we examined the effect of increasing phenylalanine intake from fruits and vegetables, containing phenylalanine 76–100 mg /100 g, compared with milk protein sources on blood phenylalanine control. This was a five-phase study (4 weeks each phase). In Phase A, patients remained on their usual diet and then were randomly allocated to start Phase B and C (an additional phenylalanine intake of 50 mg/day, then 100 mg from fruits and vegetables containing phenylalanine 76–100 mg/100 g) or Phase D and E (an additional phenylalanine intake of 50 mg/day then 100 mg/day from milk sources). There was a 7-day washout with the usual phenylalanine-restricted diet between Phase B/C and D/E. Blood phenylalanine was measured on the last 3 days of each week. If four out of six consecutive blood phenylalanine levels were >360 μmol/L in one arm, this intervention was stopped. Sixteen patients (median age 10.5 y; range 6–12 y) were recruited. At baseline, a median of 6 g/day (range: 3–25) natural protein and 60 g/day (range: 60–80) protein equivalent from protein substitute were prescribed. Median phenylalanine levels were: Phase A—240 μmol/L; Phase B—260 μmol/L; Phase C—280 μmol/L; Phase D—270 μmol/L and Phase E—280 μmol/L. All patients tolerated an extra 50 mg/day of phenylalanine from fruit and vegetables, containing phenylalanine 76–100 mg/100 g, but only 11/16 (69%) tolerated an additional 100 mg /day. With milk protein, only 8/16 (50%) tolerated an extra 50 mg/day and only 5/16 (31%) tolerated an additional 100 mg/day of phenylalanine. Tolerance was defined as maintaining consistent blood phenylalanine levels < 360 μmol/L throughout each study arm. There was a trend that vegetable protein had less impact on blood phenylalanine control than milk protein, but overall, the differences were not statistically significant (p = 0.152). This evidence supports the PKU European Guidelines cutoff that fruit and vegetables containing 76–100 mg phenylalanine/100 g should be calculated as part of the phenylalanine exchange system. Tolerance of the ‘free use’ of these fruits and vegetables depends on inter-patient variability but cannot be recommended for all patients with PKU.     

A mechanistic mathematical model of initiation and malignant transformation in sporadic vestibular schwannoma

Background A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between nonsense mutations and loss of heterozygosity (LOH).Methods Here, we present a mechanistic approach to modelling initiation and malignant transformation in schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH.Results This results in new estimates for the base-pair mutation rate u = 4.48 × 10⁻¹⁰ and the rate of LOH = 2.03 × 10⁻⁶/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation.Discussion We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.Subject terms: CNS cancer, Cancer in the nervous system     

Highlights from the Tenth World Conference on Lung Cancer

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.