Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

The relationship of gut microbiota in standard and overweight children, before and after probiotic administration

This study investigates the connection of commercial probiotics and gut microbiome health in relation to childrens' weights (standard and overweight). The study utilized a cross-over design with probiotic (brand "Yakult") intervention.The usage of probiotic foods and supplements has been widely considered part of a healthy diet by supplementing the gut microbiome with beneficial bacteria. Although the usage of probiotics is a common dietary accessory, there is limited reproducible evidence showing bacterial colonization, thus limiting long term effectiveness. We administered Yakult, a commercial probiotic composed of Lactobacillus paracasei strain Shirota, to overweight and standard weight school children in Malaysia. Using a crossover intervention study design, two groups of school children were administered the probiotic supplement or continued their typical diet in sequential 5-week intervention periods, separated by a 5-week washout period. Fecal samples were collected every five weeks over the course of the 15-week study period. The gut microbiome of each subject was analyzed using 16S rRNA gene sequencing. We observed significant differences in Lachnospiraceae, Coproccus, Roseburia, Pyramidobacter, and Bacteroides ovatus between weight classes. However, differences in overall microbiome diversity between weight classes were not found to be significant. Subjects clustered according to their relative abundance of well-known genera Bacteroides and Prevotella, regardless of age, gender, or weight class. Overall, individual-to-individual variation overshadowed trends in gut microbiome composition associated with probiotic administration.This research was supported by the Undergraduate Research Opportunities Program (UROP)

A review of the affects of worry and generalized anxiety disorder upon cardiovascular health and coronary heart disease

Published online: 16 Jan 2013OBJECTIVE: The aims of this review article are to present psychophysiological and behavioral pathways for the involvement of worry and generalized anxiety disorder (GAD) upon cardiovascular function. The review will focus on persons with and without coronary heart disease (CHD), and encompass etiological and prognostic studies. METHODS: Articles (1975–2011) reporting on GAD or worry affecting CHD prognosis or cardiovascular function were found using MEDLINE, EMBASE, SCOPUS and PsychINFO database searches, and extracted to form a narrative review. RESULTS: Available evidence in experimental and observational studies in CHD free samples consistently showed that worry was associated with diminished heart rate variability (HRV) and elevated heart rate. Worry and GAD were commonly associated with blood pressure and diagnosed hypertension or medication use in both disease-free and established CHD populations. No evidence was found to support worry being beneficial to cardiovascular function or conducive to health promoting behaviors. The literature indicated that measures of worry were associated with fatal and nonfatal CHD in seven etiological studies of initially disease-free individuals; however, females were underrepresented. Three studies reported that GAD was associated with poorer prognosis in establish CHD, independent of depression. The median GAD prevalence was 10.4% in 3266 patients across 15 studies, suggesting that GAD is marginally less common in CHD samples than is depression. CONCLUSIONS: A growing literature highlights the association between worry and development of CHD. The association between worry, GAD and CHD risk factors (e.g. blood pressure), and HRV are leading mechanisms of cardiopathogenesis that may affect cardiovascular function. Findings regarding worry and GAD in established CHD are less clear.Phillip J. Tully, Suzie M. Cosh and Bernhard T. Baun

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

BACKGROUND: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. METHODS: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. FINDINGS: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). INTERPRETATION: ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. FUNDING: UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen