Prüfung einer potentiellen strahleninduzierten Nebenschilddrüsenfunktionsstörung während einer Radioiodtherapie benigner Schilddrüsenerkrankungen

Das Ziel der vorliegenden Arbeit war die Evaluation einer potentiellen Nebenschilddrüsenfunktionsstörung unter Radioiodtherapie benigner Schilddrüsenerkrankungen. Es sollte untersucht werden, ob es in der ersten Woche unter Radioiodtherapie zu einer Veränderung in der Nebenschilddrüsenfunktion kommt. In der Klinik für Nuklearmedizin des Universitätsklinikums Gießen-Marburg GmbH, Standort Marburg, wurde eine prospektive Kohortenstudie an insgesamt 105 Probanden (75 Frauen/30 Männer, mittleres Alter 60,62 ± 14,30 Jahre) mit einer Radioiodtherapie benigner Schilddrüsenerkrankungen durchgeführt. Die 105 Probanden wurden nach ihrer Schilddrüsenerkrankung in folgende Subgruppen unterteilt: unifokale Autonomie mit 23 Patienten, multifokale Autonomie mit 8 Patienten, disseminierte Autonomie mit 37 Patienten und in die Subgruppe Autoimmunthyreopathie vom Typ Basedow (ohne endokrine Orbitopathie) bzw. Morbus Basedow (mit endokriner Orbitopathie) mit 37 Patienten. Die Konzentration des intakten Parathormons im Serum wurde direkt vor Beginn der Radioiodtherapie am Aufnahmetag, am Tag 1, 3 und 5 der stationären Radioiodtherapie und bei der ambulanten Kontrolluntersuchung einen Monat nach Beginn der Radioiodtherapie bestimmt. Bei 99 von 105 Probanden kam es unter Radioiodtherapie zu einem Abfall der Parathormonkonzentration im Serum mit einem Tiefpunkt am dritten Tag der Therapie (Abfall um 15,71 ng/l bzw. 27,54%). Die mittlere Parathormonkonzentration im Serum betrug vor Beginn der Radioiodtherapie 48,99 ± 24,05 ng/l [n = 105], am Tag 1 nach Radioiodgabe 34,09 ± 16,25 ng/l [n = 100], am Tag 3 32,74 ± 14,11 ng/l [n = 97], am Tag 5 37,02 ± 21,52 ng/l [n = 54] und bei der Nachuntersuchung einen Monat nach Beginn der Radioiodtherapie 44,62 ± 20,54 ng/l [n = 91]. Die Patienten erhielten im Mittel eine Aktivität von 1341,43 ± 459,16 MBq [n = 105] und die Herddosis der Schilddrüse unter Radioiodtherapie lag im Mittel bei 422,53 ± 245,56 Gy [n = 101]. Die einfaktorielle Varianzanalyse über alle Daten bis zum Tag 3 bestätigte den Abfall der Parathormonkonzentration im Serum (p < 0,0001). Der Student t-Test für gepaarte Stichproben ergab einen statistisch signifikanten Abfall der Mittelwerte der Parathormonkonzentration vor Therapie zu den Mittelwerten am Tag 1 (p < 0,0001) und am Tag 3 (p < 0,0001) der Therapie. Die zweifaktorielle Varianzanalyse ergab keinen signifikanten Unterschied im Abfall der Parathormonkonzentration für die Verläufe der vier Subgruppen (p = 0,32). Es ließ sich keine Korrelation zwischen dem absoluten bzw. dem relativen Parathormonabfall und der Herddosis der Schilddrüse nachweisen. Die vorliegende Arbeit zeigt erstmalig in diesem Umfang, dass es schon in den ersten Tagen nach Radioiodgabe zu einem Abfall der Parathormonkonzentration im Serum kommt, höchstwahrscheinlich aufgrund einer akuten Nebenschilddrüsenfunktionsstörung. Es wird vermutet, dass diese Störung eine Folge der ionisierenden Strahlen des 131I ist

Signatures of mutational processes in human cancer.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

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