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

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Biological Validation of Plant-derived Anti-human Colorectal Cancer Monoclonal Antibody CO17-1A

We validated expression and biological activities of plant-derived monoclonal antibody (MAb(P)) CO17-1A for its efficacy in cancer immunotherapy. PCR and immunoblot analyses demonstrated insertion and expression of heavy and light chains of MAb CO17-1A in transgenic plants, respectively. Confocal analysis revealed that MAb(P) CO17-1A was accumulated throughout the cytoplasm near the outer membrane, suggesting its secretion to the outer membrane via a default pathway. Cell ELISA analysis confirmed that the MAb(P) CO17-1A heavy and light chains in crude plant leaf samples assembled to specifically bind SW948 human colorectal carcinoma cells. Flow cytometry analysis showed that the Fc domains of both the purified MAb(P) and the mammalian- derived MAb (MAb(M)) evidenced similar binding activity to the Fc gamma RI receptor (CD64). The biological activities of both MAbs were similar, although the glycosylation pattern of MAb(P) CO17-1A is distinct from that of MAb(M). These results point to the potential use of MAb(P) CO17-1A for colorectal cancer immunotherapy

Overexpression of serum amyloid a 1 induces depressive-like behavior in mice

Alzheimer&apos;s disease (AD) is a neurodegenerative disorder characterized by loss of memory and cognitive abilities. In AD, amyloid β (Aβ) protein aggregates in the brain of patients, forming amyloid plaques. Aβ plaques are known to be surrounded by activated microglial cells. Serum amyloid A (SAA) is elevated from several hundred to 1000-fold as part of the immune response against various injuries, including trauma, infection, and inflammation. Additionally, continuous elevation of SAA is related to the development of amyloidosis. This study was designed to identify the relationship between SAA1 and AD using liver specific SAA1 overexpressing mice (TG), because SAA1 is expressed in the liver during the acute phase. We detected exogenous SAA1 expression in the brain of TG mice. This result implies that liver-derived SAA1 migrates to the brain tissues. Thus, we confirmed that the blood brain barrier (BBB) functioned normally using Evans-blue staining and CARS. Furthermore, our results show an increase in the accumulation of the 87 kDa form of Aβ in TG mice compared to wild type mice (WT). Additionally, the number of microglial cells and levels of pro-inflammatory cytokines were increased. Next, we investigated the relationship between SAA1 and depression by performing social interaction tests. The results showed that TG mice have a tendency to avoid stranger mice and an impaired social recognition. In conclusion, the SAA1 TG mouse model is a valuable model to study depression. © 2016 Elsevier B.V.