Psychosocial Experiences And Genetic Knowledge In Individuals With Pathogenic And Uncertain Tp53 Variants In The Prospective Registry Of Multiplex Testing (prompt) Cohort

Germline mutations in the TP53 gene confer increased risk of diverse malignancies in children and adults in the Li Fraumeni cancer susceptibility syndrome, a rare condition with estimated prevalence of about 1 in 3,555 in the population. The Prospective Registry of Multiplex Testing (PROMPT) study is a registry of individuals undergoing genetic testing for inherited cancer susceptibility using multi-gene panels regardless of test results and agreeing to participate in questionnaire studies about their experience. The purpose of this study was to investigate how the psychosocial experience of genetic testing and level of genetic understanding and knowledge differs for those who have a variant of uncertain significance (VUS) compared to those with a pathogenic TP53 variant. We evaluated data from 69 eligible participants from the PROMPT Study. Using an electronic survey, we assessed their TP53 knowledge and understanding with the KnowGene instrument, as well as their psychosocial experiences with the FACToR subscales. Differences in instrument performance were evaluated by variant class. Respondents with a pathogenic variant (those with Li-Fraumeni syndrome, “LFS”) had significantly higher levels of distress compared to those with a VUS. Respondents with a pathogenic variant had moderately higher levels of genetic knowledge and understanding compared to those with a VUS. This exploratory project demonstrates the need for more comprehensive work assessing the burden of LFS on individuals testing positive for pathogenic variants in the TP53 gene on germline genetic evaluation

Küstenschutzwälder im Interessenskonflikt zwischen Nutzung und ökologischer Funktion - der "Gespensterwald Nienhagen" in Mecklenburg-Vorpommern

Im Gespensterwald Nienhagen als Teil des Küstenschutzwaldes Nienhäger Holz (Ostseebad Nienhagen, Mecklenburg-Vorpommern) wurden 2012 die Böden in Abhängigkeit von der Nutzungsart (Hochwald, Verjüngung und Acker als Referenz) und dem Abstand vom Kliff untersucht. Anhand der Gehalte an organischer Substanz und der Aggregierungseigenschaften (Aggregatgrößenverteilung und Aggregatstabilität) wurden deutliche Differenzierungen nachgezeichnet, die den nachteiligen Einfluss zunehmender Trittbelastung im Kliffbereich belegen

Viral Linkage in HIV-1 Seroconverters and Their Partners in an HIV-1 Prevention Clinical Trial

Characterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519) was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners.We obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥ 50%. Adjudicators classified each seroconversion, finding 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%). Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters.In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process

Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation.

Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations

An immune-based biomarker signature is associated with mortality in COVID-19 patients

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN–, type II IFN–, and NF-κB–dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome