Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM

Cooperative Switching in Large‐Area Assemblies of Magnetic Janus Particles

Magnetic Janus particles (MJPs) have received considerable attention for their rich assembly behavior and their potential technological role in applications ranging from simple magnetophoretic displays to smart cloaking devices. However, further progress is hampered by the lack of predictive understanding of the cooperative self‐assembly behavior of MJPs and appropriate dynamic control mechanisms. In this paper, a detailed experimental and theoretical investigation into the magnetically directed spatiotemporal self‐assembly and switching of MJPs is presented. For this purpose, a novel type of MJPs with defined hemispherical compartments carrying superparamagnetic iron oxide nanoparticles as well as a novel simulation model to describe their cooperative switching behavior is established. Combination of the theoretical and experimental work culminates in a simple method to direct assemblies of MJPs, even at high particle concentrations. In addition, a magnetophoretic display with switchable MJPs is developed on the basis of the theoretical findings to demonstrate the potential usefulness of controlled large‐area assemblies of magnetic Janus particles.Anisotropic particles that have one hemisphere selectively loaded with magnetite nanoparticles rotate in response to magnetic fields as indicated by visually observable color changes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155896/1/adfm201907865-sup-0001-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155896/2/adfm201907865.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155896/3/adfm201907865_am.pd

Single cell genome analysis supports a link between phagotrophy and primary plastid endosymbiosis

Two cases of primary plastid endosymbiosis are known. The first occurred ca. 1.6 billion years ago and putatively gave rise to the canonical plastid in algae and plants. The second is restricted to a genus of rhizarian amoebae that includes Paulinella chromatophora. Photosynthetic Paulinella species gained their plastid from an α-cyanobacterial source and are sister to plastid-lacking phagotrophs such as Paulinella ovalis that ingest cyanobacteria. To study the role of feeding behavior in plastid origin, we analyzed single-cell genome assemblies from six P. ovalis-like cells isolated from Chesapeake Bay, USA. Dozens of contigs in these cell assemblies were derived from prey DNA of α-cyanobacterial origin and associated cyanophages. We found two examples of horizontal gene transfer (HGT) in P. ovalis-like nuclear DNA from cyanobacterial sources. This work suggests the first evidence of a link between feeding behavior in wild-caught cells, HGT, and plastid primary endosymbiosis in the monophyletic Paulinella lineage

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure : Pooled Analysis of 4 Clinical Studies

Background This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). Methods Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. Results Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. Conclusion Based on integrated data from 4 clinical studies, including long-term follow-up forPeer reviewe

Foldable structures made of hydrogel bilayers

We discuss self-folding of a thin sheet by using patterned hydrogel bilayers, which act as hinges connecting flat faces. Folding is actuated by heterogeneous swelling due to different crosslinking densities of the polymer network in the two layers. Our analysis is based on a dimensionally reduced plate model, obtained by applying a recently developed theory [1], which provides us with an explicit connection between (three-dimensional) material properties and the curvatures induced at the hinges. This connection offers a recipe for the fabrication and design of the bilayers, by providing the values of the cross-linking density of each layer that need to be imprinted during polymerization in order to produce a desired folded shape upon swelling

Carcinoma ex Pleomorphic Adenoma of the Salivary Glands: Distinct Clinicopathologic Features and Immunoprofiles Between Subgroups According to Cellular Differentiation

In carcinoma ex pleomorphic adenoma (CXPA), pleomorphic adenoma (PA) and diverse carcinoma components showing luminal (ductal) or non-luminal (myoepithelial) differentiation coexist. To elucidate the clinicopathological implications of cellular differentiation in CXPA and the potential role of p53, vascular endothelial growth factor (VEGF), c-erbB-2, c-kit, and glucose transporter 1 (Glut-1) in carcinogenesis, we analyzed 11 CXPAs with luminal differentiation (CXPAs-LD) and 6 CXPAs with non-luminal differentiation (CXPAs-NLD) and compared protein expressions in residual PAs and carcinomas by immunohistochemistry. Among the CXPAs-LD, 5 were invasive and 8 were histologically high-grade tumors. The 5-year survival rate was 72.7%. P53, c-erbB-2, VEGF, and Glut-1 were more immunoreactive in carcinoma components than in PAs (P = 0.008, 0.004, 0.002, and 0.024, respectively); c-erbB-2 overexpression was associated with high histological grade (P = 0.024). Carcinoma components frequently lacked c-kit expression (P = 0.009). CXPAs-NLD were all low-grade and invasive with a larger mean tumor size (5.2 cm) than CXPAs-LD (3.3 cm) (P = 0.040). The patients remained disease-free without significant immunohistochemical expression. The immunoprofiles and clinical course of CXPA differed according to cellular differentiation. Therefore, it is important to report the histological subtype and to assess potential biomarkers in diagnostic and therapeutic trials

Knowledge user survey and Delphi process to inform development of a new risk of bias tool to assess systematic reviews with network meta-analysis (RoB NMA tool)

Background: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted. Objectives: Conduct (a) a Delphi process to determine expert opinion on an item's inclusion and (b) a knowledge user survey to widen its impact. Design: Cross-sectional survey and Delphi process. Methods: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users' views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks. Results: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors' conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines. Conclusions: This Delphi process and knowledge user survey informs the development of the RoB NMA tool