Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer's disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE ε4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling

A network medicine approach to quantify distance between hereditary disease modules on the interactome

We introduce a MeSH-based method that accurately quantifies similarity between heritable diseases at molecular level. This method effectively brings together the existing information about diseases that is scattered across the vast corpus of biomedical literature. We prove that sets of MeSH terms provide a highly descriptive representation of heritable disease and that the structure of MeSH provides a natural way of combining individual MeSH vocabularies. We show that our measure can be used effectively in the prediction of candidate disease genes. We developed a web application to query more than 28.5 million relationships between 7,574 hereditary diseases (96% of OMIM) based on our similarity measure

Phrase Frequency Effects in Language Production

A classic debate in the psychology of language concerns the question of the grain-size of the linguistic information that is stored in memory. One view is that only morphologically simple forms are stored (e.g., ‘car’, ‘red’), and that more complex forms of language such as multi-word phrases (e.g., ‘red car’) are generated on-line from the simple forms. In two experiments we tested this view. In Experiment 1, participants produced noun+adjective and noun+noun phrases that were elicited by experimental displays consisting of colored line drawings and two superimposed line drawings. In Experiment 2, participants produced noun+adjective and determiner+noun+adjective utterances elicited by colored line drawings. In both experiments, naming latencies decreased with increasing frequency of the multi-word phrase, and were unaffected by the frequency of the object name in the utterance. These results suggest that the language system is sensitive to the distribution of linguistic information at grain-sizes beyond individual words

Relative contribution of various chronic diseases and multi-morbidity to potential disability among Dutch elderly

BACKGROUND: The amount of time spent living with disease greatly influences elderly people’s wellbeing, disability and healthcare costs, but differs by disease, age and sex. METHODS: We assessed how various single and combined diseases differentially affect life years spent living with disease in Dutch elderly men and women (65+) over their remaining life course. Multistate life table calculations were applied to age and sex-specific disease prevalence, incidence and death rates for the Netherlands in 2007. We distinguished congestive heart failure, coronary heart disease (CHD), breast and prostate cancer, colon cancer, lung cancer, diabetes, COPD, stroke, dementia and osteoarthritis. RESULTS: Across ages 65, 70, 75, 80 and 85, CHD caused the most time spent living with disease for Dutch men (from 7.6 years at age 65 to 3.7 years at age 85) and osteoarthritis for Dutch women (from 11.7 years at age 65 to 4. 8 years at age 85). Of the various co-occurrences of disease, the combination of diabetes and osteoarthritis led to the most time spent living with disease, for both men (from 11.2 years at age 65 to 4.9 -years at age 85) and women (from 14.2 years at age 65 to 6.0 years at age 85). CONCLUSIONS: Specific single and multi-morbid diseases affect men and women differently at different phases in the life course in terms of the time spent living with disease, and consequently, their potential disability. Timely sex and age-specific interventions targeting prevention of the single and combined diseases identified could reduce healthcare costs and increase wellbeing in elderly people

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Longitudinal changes in sedentary time and physical activity during adolescence

BACKGROUND: Low levels of physical activity and high time spent in sedentary activities have been associated with unfavourable health outcomes in adolescents. During adolescence, physical activity declines and sedentary time increases, however little is known about whether the magnitude of these changes differs within or between school-time, after-school time, or at weekends. METHODS: Adolescents (n = 363) participating in the PEACH (Personal and Environmental Associations with Children’s Health) project provided accelerometer data at 12 and 15 years of age. Data were collected in 2008/2009 and 2012/2013. Time spent sedentary (<100 cpm), in light physical activity (LPA (100-2295 cpm) and in moderate to vigorous physical activity (MVPA: ≥ 2296 cpm) were generated for school-time, after-school time and for weekends using school-specific start and finish times. All data were analysed in 2014. RESULTS: The proportion of time spent sedentary significantly increased during school (+8.23%, 95% CI = 7.35 to 9.13), after-school (+6.99%, 95% CI = 5.91 to 8.07) and at weekends (+6.86%, 95% CI = 5.10 to 8.62). A parallel decrease was found in the proportion of time spent in LPA during school (-7.62%, 95% CI = -8.26 to -6.98), after-school (-7.01%, 95% CI = -7.74 to -6.28) and at weekends (-6.72%, 95% CI = -7.80 to -5.65). The proportion of time spent in MVPA remained relatively stable during school (-0.64, 95% CI = -1.11 to -0.18), after-school (0.04%, 95% CI = -0.58 to 0.67) and at weekends (-0.14%, 95% CI = -1.18 to 0.90). CONCLUSIONS: Objectively measured sedentary time increased between 12 and 15 years of age during-school, after-school, and at weekends, suggesting that interventions aiming to reduce the age-associated changes in sedentary time are needed in all three time contexts. Future work should identify which sedentary activities change more than others to inform interventions which aim to minimise the increase in time spent sedentary during adolescence

Subclinical Hypothyroidism has Little Influences on Muscle Mass or Strength in Elderly People

Sarcopenia, the age-related decline in muscle mass, affects the muscle strength and muscle quality, and these changes decrease functional capacity. The prevalence of thyroid dysfunction increases with age, and changes in thyroid hormone level lead to neuromuscular deficits. We investigated the effects of subclinical hypothyroidism on the muscle mass, strength or quality in elderly people. One thousand one hundred eighteen subjects aged ≥65 yr were randomly selected from a local population and classified into a euthyroid (280 men and 358 women), subclinically hypothyroid (61 men and 75 women), or overtly hypothyroid (7 men and 16 women) group. Although women with subclinical hypothyroidism had a higher prevalence of sarcopenia, defined according to the ratio of appendicular skeletal muscle mass to the square of height, muscle mass, strength or quality did not differ in relation to thyroid status in men or in women. Multivariate analysis including age, diabetes, hypertension, acute coronary event, alcohol, smoking, presence of pain, physical activity score, and lipid profile, showed that thyroid-stimulating hormone level was not associated with muscle mass, strength or quality. In conclusion, subclinical hypothyroidism has little influences on muscle mass, strength or quality, and may not be associated with sarcopenia