Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Carbon-Fibre-Reinforced SiC Composite (C/SiSiC) as an Alternative Material for Endoprosthesis: Fabrication, Mechanical and In-Vitro Biological Properties

Particle-induced periprosthetic osteolysis and subsequent aseptic implant loosening are a major cause of compromising the long-term results of total joint replacements. To date, no implant has been able to mirror radically the tribological factors (friction/lubrication/wear) of in vivo tribological pairings. Carbon-Fibre Reinforced SiC-Composites (C/SiSiC), a material primarily developed for brake technology, has the opportunity to fulfil this requirement. Until now, the material itself has not been used in medicine. The aim of this investigation was to test the suitability of C/SiSiC ceramics as a new material for bearing couples in endoprosthetics. After the preparation of the composites flexural strength was determined as well as the Young’s-modulus and the coefficient of friction. To investigate in vitro biological properties, MG 63 and primary human osteoblasts were cultured on C/SiSiC composites. To review the proliferation, the cytotoxicity standardized tests were used. The cell morphology was observed by light microscopy, ESEM, confocal and 3D-laserscanning microscopy. C/SiSiC possesses a high resistance to wear. Cells exhibited no significant alterations in morphology. Vitality was not impaired by contact with the ceramic composite. There was no higher cytotoxicity to observe. Regarding these results, C/SiSiC ceramics seem to be biologically and mechanically appropriate for orthopaedic applications

The stability and functional properties of proteoliposomes mixed with dextran derivatives bearing hydrophobic anchor groups

Liposomes composed of Escherichia coli phospholipid were coated with polysaccharides bearing hydrophobic palmitoyl anchors. The effect on the stability of liposomes without or with integral membrane proteins was investigated. A high concentration of hydrophobized dextrans protected the liposomes against detergent degradation, decreased the fluidity of the membranes, prevented fusion of the liposomes and enhanced their stability. Proteoliposomes containing beef heart cytochrome-c oxidase and the lactose transport carrier of E. coli were similarly affected by coating with the dextrans. Under these conditions both membrane proteins were still active. Long-term stability of the coated liposomes was obtained only in the absence of the integral membrane proteins

West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer

PURPOSE The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC). PATIENTS AND METHODS Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)(90)/cyclophoshamide (C)(600) followed by four cycles of docetaxel (T)(100) or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined. RESULT Of the 3,198 registered patients, 348 (RS <= 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v60.8%; pNO, 58.2% v59.5%; pT1, 57.6% v52.3%; HR positive, 81.4% v82.2%; RS greater than 25 [in H.R-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status. CONCLUSION In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease. (C) 2019 by American Society of Clinical Oncolog