Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations ...are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
The purpose of this study was to assess the prognostic impact of age in patients with triple-negative breast cancer (TNBC). 1,732 patients with primary TNBC were analyzed. Five age cohorts (≤30, ...31–40, 41–50, 51–60, and >60 years) at diagnosis were correlated with clinical/pathological parameters. Univariate and multivariate analyses were used to examine the effect of age on disease-free (DFS), distant disease-free (DDFS), and overall survival (OS). In patients with TNBC, increasing age at diagnosis was inversely correlated with tumor grade (
P
< 0.0001); likelihood of being non-Caucasian (
P
= 0.0001); likelihood of getting chemotherapy (
P
< 0.0001); and positively correlated with DFS (
P
= 0.0003); DDFS (
P
< 0.0001); and OS (
P
< 0.0001). The median DFS for patients 31–40 and older than 60 years was 4 years 95 % confidence interval (95 % CI) 2–5 and 8 years (95 % CI 5–14, respectively,
P
= 0.0003). The DDFS and OS were also statistically significantly shorter for younger patients. In multivariate analysis, tumor size, nodal stage, tumor grade, and age remained significant independent prognostic variables. Clinical characteristics of TNBC differ by age group, patients ≤40 years have poorer survival despite more aggressive systemic therapy.
The objective of this study was to examine whether the plane of nutrition of cows at a critical time for fetal skeletal muscle and adipose tissue development would affect meat quality and carcass ...composition of offspring. To alter maternal nutrition, beef cows were placed on improved pasture (IP) or native range (NR) pasture from 120 to 150 through 180 to 210
days of gestation. Esophageal extrusa samples collected from cows grazing IP varied from 11.1% crude protein of organic matter early in the test period to 6.0% crude protein of organic matter at the end of the grazing period; whereas, extrusa samples of cows grazing NR ranged from 6.5% crude protein of organic matter during early grazing to 5.4% crude protein of organic matter at the end of the grazing period. Steers were slaughtered and carcass characteristics were collected. Warner–Bratzler shear force was performed on longissumus steaks, western blotting was used to measure proteolysis, and myosin isoform typing was performed. Improved pasture steers had heavier live and hot carcass weights. Tenderness was greater in IP compared to NR steers. No difference in calpastatin content and troponin-T degradation was observed between treatments. The 12th rib fat thickness was greater for IP than for NR steers. Subcutaneous adipose tissue of IP steers tended to have a greater number of cells per field of view than NR steers. Data show improving nutritional status of cows during mid to late gestation affects tenderness, adipose tissue deposition and growth in steers.
Protein glycosylation events that happen early in the secretory pathway are often dysregulated during tumorigenesis. These events can be probed, in principle, by monosaccharides with bioorthogonal ...tags that would ideally be specific for distinct glycan subtypes. However, metabolic interconversion into other monosaccharides drastically reduces such specificity in the living cell. Here, we use a structure-based design process to develop the monosaccharide probe NE-(S)-azidopropionylgalactosamine (GalNAzMe) that is specific for cancer-relevant Ser/Thr(O)–linked N-acetylgalactosamine (GalNAc) glycosylation. By virtue of a branched N-acylamide side chain, GalNAzMe is not interconverted by epimerization to the corresponding N-acetylglucosamine analog by the epimerase N-acetylgalactosamine–4-epimerase (GALE) like conventional GalNAc–based probes. GalNAzMe enters O-GalNAc glycosylation but does not enter other major cell surface glycan types including Asn(N)-linked glycans. We transfect cells with the engineered pyrophosphorylase mut-AGX1 to biosynthesize the nucleotidesugar donor uridine diphosphate (UDP)-GalNAzMe from a sugar-1-phosphate precursor. Tagged with a bioorthogonal azide group, GalNAzMe serves as an O-glycan–specific reporter in superresolution microscopy, chemical glycoproteomics, a genome-wide CRISPR-knockout (CRISPR-KO) screen, and imaging of intestinal organoids. Additional ectopic expression of an engineered glycosyltransferase, “bump-and-hole” (BH)–GalNAc-T2, boosts labeling in a programmable fashion by increasing incorporation of GalNAzMe into the cell surface glycoproteome. Alleviating the need for GALE-KO cells in metabolic labeling experiments, GalNAzMe is a precision tool that allows a detailed view into the biology of a major type of cancer-relevant protein glycosylation.
Transcriptional profiling technologies that simultaneously measure the expression of thousands of mRNA species represent a powerful new clinical research tool. Similar to previous laboratory ...analytical methods including immunohistochemistry, PCR and in situ hybridization, this new technology may also find its niche in routine diagnostics. Outcome predictors discovered by these methods may be quite different from previous single-gene markers. These novel tests will probably combine the information embedded in the expression of multiple genes with mathematical prediction algorithms to formulate classification rules and predict outcome. The performance of machine learning-algorithm-based diagnostic tests may improve as they are trained on larger and larger sets of samples, and several generations of tests with improving accuracy may be introduced sequentially. Several gene-expression profiling–technology platforms are mature enough for clinical testing. The most important next step that is needed for further progress is the development and validation of multigene predictors in prospectively designed clinical trials to determine the true accuracy and clinical value of this new technology. This manuscript reviews methodological and statistical issues relevant to clinical trial design to discover and validate multigene predictors of response to therapy.
To determine aggregate outcomes and prognostic covariates in patients with recurrent glioma enrolled onto phase II chemotherapy trials.
Patients from eight consecutive phase II trials included 225 ...with recurrent glioblastoma multiforme (GBM) and 150 with recurrent anaplastic astrocytoma (AA). Their median age was 45 years (range, 15 to 82 years) and their median Karnofsky performance score was 80 (range, 60 to 100). Prognostic covariates were analyzed with respect to tumor response, progression-free survival (PFS), and overall survival (OS) by multivariate logistic and Cox proportional hazards regression analyses.
Overall, 34 (9%) had complete or partial response, whereas 80 (21%) were alive and progression-free at 6 months (APF6). The median PFS was 10 weeks and median OS was 30 weeks. Histology was a robust prognostic factor across all outcomes. GBM patients had significantly poorer outcomes than AA patients. The APF6 proportion was 15% for GBM and 31% for AA, whereas the median PFS was 9 weeks for GBM and 13 weeks for AA. Results were also significantly poorer for patients with more than two prior surgeries or chemotherapy regimens.
Histology is a dominant factor in determining outcome in patients with recurrent glioma enrolled onto phase II trials. Future trials should be designed with separate histology strata.
•We value four Non-Timber Forest Products from the Eastern Arc Mountains in Tanzania.•We transfer spatially explicit models of NTFP collection across a wide area.•The total annual benefit flow is ...approximately USD 42million.•Households in the lowest income quartiles in the area depend most on these products.•Conservation initiatives need to be coordinated with poverty and energy policies.
Understanding the spatial distribution of the quantity and economic value of Non-Timber Forest Product (NTFP) collection gives insight into the benefits that local communities obtain from forests, and can inform decisions about the selection of forested areas that are eligible for conservation and enforcement of regulations. In this paper we estimate transferable household production functions of NTFP extraction in the Eastern Arc Mountains (EAM) in Tanzania, based on information from seven multi-site datasets related to the behaviour of over 2000 households. The study shows that the total benefit flow of charcoal, firewood, poles and thatch from the EAM to the local population has an estimated value of USD 42million per year, and provides an important source of additional income for local communities, especially the poorest, who mainly depend on subsistence agriculture. The resulting map of economic values shows that benefits vary highly across space with population density, infrastructure and resource availability. We argue that if further restrictions on forest access to promote conservation are considered, this will require additional policies to prevent a consequent increase in poverty, and an enforced trade-off between conservation and energy supply to rural and urban households.
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