Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

MiR-146a-5p Expression in Peripheral CD14+ Monocytes from Patients with Psoriatic Arthritis Induces Osteoclast Activation, Bone Resorption, and Correlates with Clinical Response

In psoriatic arthritis (PsA), progressive bone destruction is mediated by monocyte-derived osteoclasts. MicroRNAs (miRNAs) regulate many pathophysiological processes; however, their function in PsA patient monocytes has not been examined. This study aims to address whether specific miRNAs in CD14+ monocytes and monocyte-derived osteoclasts cause active osteoclastogenesis in PsA patients. Candidate miRNAs related to monocyte activation (miR-146a-5p, miR-146b-5p and miR-155-5p) were measured in circulatory CD14+ monocytes collected from 34 PsA patients, 17 psoriasis without arthritis (PsO) patients, and 34 normal controls (NCs). CD14+ monocytes were cultured with media containing TNF-&alpha; and RANKL to differentiate into osteoclasts. Osteoclast differentiation and bone resorption were measured by TRAP immunostaining and dentin slice resorption, respectively. The results showed that the miR-146a-5p expression was higher in PsA patient-derived CD14+ monocytes compared to PsO and NCs. Activation and bone resorption were selectively enhanced in osteoclasts from PsA patients, but both were abrogated by RNA interference against miR-146a-5p. More importantly, after clinical improvement using biologics, the increased miR-146a-5p expression in CD14+ monocytes from PsA patients was selectively abolished, and associated with blood CRP level. Our findings indicate that miR-146a-5p expression in CD14+ monocytes derived from PsA patients correlates with clinical efficacy, and induction of osteoclast activation and bone resorption

TNF-&alpha; Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-&alpha; blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-&alpha; milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-&alpha; exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-&alpha; in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-&alpha; but not IL-17. We conclude that TNF-&alpha; recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA

Microstructural and Chemical Investigations of Presolar Silicates from Diverse Stellar Environments

We report the structural and chemical investigation of nine presolar silicate grains from the CH3/CB(b)3 chondrite Isheyevo and CR2 chondrite Northwest Africa (NWA) 801. Five of these grains belong to group 1, likely condensed in low- to intermediate-mass asymptotic giant branch (AGB) stars, super-AGB stars, or core-collapse supernovae, while the remaining four grains belong to group 4 and have a supernova origin. The advanced transmission electron microscopy and associated electron spectroscopy analyses show a diverse range of chemical and structural compositions for presolar silicates. Two GEMS (glass with embedded metal and sulfide)-like silicates, each from different groups, condensed under nonequilibrium conditions in stellar outflows. Two nonstoichiometric silicates from group 1 have dissimilar formation and alteration histories. An amorphous silicate from group 1 with olivine-like [(Mg,Fe)(2)SiO4] composition likely formed as a crystalline olivine that subsequently amorphized in the interstellar medium. An oldhamite (CaS) grain within a stoichiometric enstatite (MgSiO3) from group 1 probably formed by heterogeneous condensation in circumstellar outflows. Of the two crystalline grains from group 4, one is an antigorite [(Mg,Fe)(3)Si2O5(OH)(4)], while the other is a nontronite [Na,Fe-2(Si,Al)(4)O-10(OH)(2).nH(2)O], both formed as a crystalline forsterite and later altered to have hydrated silicate composition. A group-4 silicate has a chemical composition similar to a low Ca-pyroxene [(Ca,Mg)(Si,Al)(2)O-6]. Our data imply that presolar grains from different groups can have a similar range of grain-formation conditions.We thank Vikram Goyal at Physical Research Laboratory (PRL), India for his assistance on the NanoSIMS; Daniel Wielandt and Lalit Shukla for initial NanoSIMS measurements at PRL; Takeshi Kasama and Berit Wenzell at DTU-CEN, Copenhagen, Keulen Nynke and Alaei Mojagan at GEUS, Copenhagen, Deepak Panda at PRL, Yoshiyuki Iizuka at Academia Sinica, Taipei, and Zina Fihl at SNM, Copenhagen for help with the SEM. We also thank Larry Nittler at the Carnegie Institution for Science for help on the L'image software and interpretation of some of the grain data. Funding for this project was provided by the Carlsberg Foundation (CF18-1105), the Danish National Research Foundation (DNRF97), and the European Research Council (ERC Advanced grant Agreement, #833275-DEEPTIME) grants to M.B. The authors acknowledge the use of instrumentation provided by the National Facility ELECMI ICTS ("Division de Microscopia Electronica," Universidad de Cadiz, DME-UCA). L.L. acknowledges funding from the Andalusian regional government (FEDER-UCA-18-106613), the European Union's Horizon 2020 research and innovation program (grant agreement 823717-ESTEEM3), and the Spanish Ministerio de Economia y Competitividad (PID2019-107578GA-I00)

RGB-Stack Light Emitting Diode Modules with Transparent Glass Circuit Board and Oil Encapsulation

The light emitting diode (LED) is widely used in modern solid-state lighting applications, and its output efficiency is closely related to the submounts’ material properties. Most submounts used today, such as low-power printed circuit boards (PCBs) or high-power metal core printed circuit boards (MCPCBs), are not transparent and seriously decrease the output light extraction. To meet the requirements of high light output and better color mixing, a three-dimensional (3-D) stacked flip-chip (FC) LED module is proposed and demonstrated. To realize light penetration and mixing, the mentioned 3-D vertically stacking RGB LEDs use transparent glass as FC package submounts called glass circuit boards (GCB). Light emitted from each GCB stacked LEDs passes through each other and thus exhibits good output efficiency and homogeneous light-mixing characteristics. In this work, the parasitic problem of heat accumulation, which caused by the poor thermal conductivity of GCB and leads to a serious decrease in output efficiency, is solved by a proposed transparent cooling oil encapsulation (OCP) method