Combinations of low-frequency genetic variants might predispose to familial pancreatic cancer

Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants

Phenotypic and molecular analysis of a mouse insertional mutation with axonal reorganization in hippocampal brain

In dieser Arbeit wurde ein neues epileptisches Maus-Modell generiert und analysiert, das im adulten Hippocampus ab einem Alter von 6 Monaten massives aberrantes Moosfaser-Wachstum zeigt. Die Mutation dieses Maus-Modells besteht aus einer intronischen Insertion transgener DNA (TC) in das Phospholipase C-beta 1 -Gen der Maus (PLC-ß1TC-/- -Mutation), die zu einer vollständig penetranten Spleiß-Mutation und zu einem kompletten Verlust von PLC-ß1-Expression führt. PLC-ß1TC-/- -Mäuse zeigen ab einem Alter von 6 Monaten eine auffällige epileptiforme Hyperexzitabilität, Verhaltensauffälligkeiten im Radial-Labyrinth- und im "Offenen Feld" -Experiment, eine männliche Infertilität und eine Störung des weiblichen Brutpflegeverhaltens, sowie juvenil eine Wachstumsretardierung und eine erhöhte postnatale Mortalität. Morphologisch entwickeln PLC-ß1TC-/- -Mutanten einen spezifischen Verlust funktioneller NMDA-Rezeptoren im Stratum oriens der hippocampalen Region CA1, zeigen aberrantes Moos- und Calretinin- Faser-Wachstum, neuronalen Zelltod (Apoptose), und eine Reduktion hippocampaler PKC-Aktivität. In der vorliegenden Arbeit wurde gezeigt, dass die Ausprägung des phänotypischen Verhaltens in adulten PLC-ß1TC-/--Mäusen zeitlich mit der Entwicklung der aberranten Moosfaser-Projektionen korreliert, und dass axonales Wachstum und reaktive Synaptogenese eine funktionale Rolle bei der Epileptogenese spielen. Kim und Mitarbeiter (1997) konnten durch die Analyse Ihres homolog rekombinierten PLC-ß1-/- -Maus Modells zwar bereits zeigen, dass PLC-ß1 im murinen Hippocampus und im cerebralen Cortex die Transduktion cholinerger Signale über die Zytoplasmamembran vermittelt, aber der adulte Phänotyp der PLC-ß1TC-/- -Mäuse wurde bisher noch nicht beschrieben. In der vorliegenden Arbeit wird postuliert, dass die Zerstörung der PLC-ß1-vermittelten Signal-Transduktion zu einer funktionalen cholinergen Denervierung des murinen Hippocampus führt, und so die axonale Remodellierung des adulten Hippocampus und die epileptiforme Hyperexzitabilität induziert

ATM mutations in familial pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer related death in Germany by 2030. Despite extensive research in recent years, PDAC still has a dismal prognosis. About 5-10% of PDAC cases accumulate in families, due to the familial pancreatic cancer syndrome, other hereditary cancer syndromes or hereditary pancreatic dysfunctionality syndromes. Families with at least two first-degree relatives affected with PDAC without fulfilling the criteria of other cancer syndromes are defined as familial pancreatic cancer (FPC). So far BRCA1, BRCA2, CDKN2A, PALB2, CHEK2 have been identified as susceptibility genes for FPC, but predisposing germline mutations in these genes have been identified in only about 10% of FPC families. Previously, it was hypothesized that the Ataxia telangiectasia mutated (ATM) gene might also be a low penetrance FPC susceptibility gene. Therefore, we analysed 35 FPC families of the National Case Collection for familial pancreatic cancer (FaPaCa) registry by Whole Genome Sequencing, Sanger Sequencing and Multiplex ligation-dependent probe amplification (MLPA) to determine the role of ATM in FPC. A deleterious ATM germline mutation (X175Y) was detected 1 of these 35 FPC families according to a prevalence of 2.9%. Deleteriousness of the mutation tested positively using MutationTaster, PolyPhen2, SIFT and PROVEAN. ATM can be considered as a low penetrance FPC susceptibility gene, which might also predispose to other cancers despite PDAC. Further studies are needed to clarify whether there might be a genotype/phenotype correlation

Supraspinatus muscle elasticity measured with real time shear wave ultrasound elastography correlates with MRI spectroscopic measured amount of fatty degeneration

Background: Fatty Degeneration (FD) of the rotator cuff muscles influences functional and anatomical outcome after rotator cuff repair. The MRI based estimation of fatty degeneration is the gold standard. There is some evidence that Ultrasound elastography (EUS) can detect local differences of tissue stiffness in muscles and tendons. Shear-wave elastography (SWE) was evaluated to determine the extent to which shear wave velocity was associated with measures of fatty degeneration. MRI-spectroscopic fat measurement was used as a reference to quantify the amount of fat in the muscle belly. Methods: Forty-two patients underwent SWE of the supraspinatus muscles at its thickest diameter. After ultrasound evaluation an MRI-spectroscopic fat measurement of the supraspinatus muscle was performed using the SPLASH-technique. A gel filled capsule was used to locate the measured area in the MRI. The values of shear wave velocity (SWV) measured with SWE and spectroscopic fat measurement were correlated statistically using Pearson’s correlation test. Results: Correlation of the fat amount measured with MRI-spectroscopy and the SWV measured with SWE was ρ =0.82. Spectroscopic measured fat ratio of the supraspinatus muscle ranged from 0% to 77.41% and SWV from 1.59 m/s to 5.32 m/s. In 4 patients no sufficient SWE could be performed, these individuals showed a larger diameter of the overlying soft tissue. SWV measured with SWE showed a good correlation with MRI spectroscopic fat amount of the supraspinatus muscle. Conclusion: These preliminary data suggest that SWE may be a sufficient tool in detecting and estimating the amount of fatty degeneration in the supraspinatus muscle in real time. Large overlying soft tissue may be a limitation in performing sufficient EUS

Toll-like receptor 5 tunes hepatic and pancreatic stellate cells activation

Objective Stellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin from invading mobile bacteria.Design Human hepatic and pancreatic stellate cells were activated by the administration of transforming growth factor-beta (TGF-β). TLR5 was transiently knocked down by short-interference RNA transfection. Reverse Transcription-quantitativePCR and western blot were performed to analyse the transcript and protein level of TLR5 and the transition players. Fluorescence microscopy was performed to identify these targets in spheroids and in the sections of murine fibrotic liver.Results TGF-β-activated human hepatic and pancreatic stellate cells showed an increase of TLR5 expression. TLR5 knockdown blocked the activation of those stellate cells. Furthermore, TLR5 busted during murine liver fibrosis and co-localised with the inducible Collagen I. Flagellin suppressed TLR5, COL1A1 and ACTA2 expression after the administration of TGF-β. Instead, the antagonist of TLR5 did not block the effect of TGF-β. Wortmannin, a specific AKT inhibitor, induced TLR5 but not COL1A1 and ACTA2 transcript and protein level.Conclusion TGF-β-mediated activation of hepatic and pancreatic stellate cells requires the over-expression of TLR5. Instead, its autonomous signalling inhibits the activation of the stellate cells, thus prompting a signalling through different regulatory pathways

Krisenmanagement - Lehrbuch für den Öffentlichen Gesundheitsdienst

Das Lehrbuch soll Mitarbeitern/innen in Gesundheitsämtern, aber auch aus anderen Einrichtungen des ÖGD, praktische Hinweise geben, wie sie sich zielgerecht auf die Gefahrenabwehr in Krisensituationen vorbereiten können, und Grundlagen des Krisenmanagements vermitteln. Neben fachlichen Gesichtspunkten werden insbesondere Handlungsempfehlungen für die Einsatzplanung und Stabsarbeit gegeben. Checklisten ergänzen das Lehrbuch als praktische Hilfsmittel.Die in diesem einzigartigen Lehrbuch zusammengefassten Inhalte beruhen auf jahrelanger theoretischer Auseinandersetzung und praktischer Erfahrung der Autoren/innen im ÖGD