Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation through vesicular engulfment of obsolete, damaged or harmful cytoplasmic components. While autophagy regulates cellular homeostasis during development and in youth, there is mounting evidence that autophagy becomes increasingly dysfunctional with age. Recent work in Caenorhabditis elegans even suggests that late‐life dysfunctional autophagy exhibits detrimental effects that drive the ageing process. Other studies link elevated autophagy closely to increased health and longevity. This review aims to put these apparently opposing views into perspective and define our current understanding of the role of autophagy during ageing.

Aging describes the age-dependent decline in the physiological functions of an organism, which affects fitness and predisposes for age-related diseases.A prominent feature of aging is the impairment of cellular homeostasis, which contributes to the emergence of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease [1].One critical process that maintains cellular metabolism and homeostasis is macroautophagy (referred here to as autophagy).This highly conserved bulk degradation program engulfs dysfunctional organelles and misfolded proteins by double membrane structures to form autophagosomes.The subsequent fusion of autophago-

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4 Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

Faithful DNA repair is essential to maintain genome integrity. Ultraviolet (UV) irradiation elicits both the recruitment of DNA repair factors and the deposition of histone marks such as monoubiquitylation of histone H2A at lesion sites. Here, we report how a ubiquitin E3 ligase complex specific to DNA repair is remodeled at lesion sites in the global genome nucleotide excision repair (GG-NER) pathway. Monoubiquitylation of histone H2A (H2A-ubiquitin) is catalyzed predominantly by a novel E3 ligase complex consisting of DDB2, DDB1, CUL4B, and RING1 B (UV RING1 B complex) that acts early during lesion recognition. The H2A-ubiquitin binding protein ZRF1 mediates remodeling of this E3 ligase complex directly at the DNA lesion site, causing the assembly of the UV-DDB-CUL4A E3 ligase complex (DDB1-DDB2- CUL4A-RBX1). ZRF1 is an essential factor in GG-NER, and its function at damaged chromatin sites is linked to damage recognition factor XPC. Overall, the results shed light on the interplay between epigenetic and DNA repair recognition factors at DNA lesion sites.

A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., α, β, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12α promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12α expression. Promoter methylation of AKAP12α correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12α promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT- and HDAC-inhibitors reactivates AKAP12α expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12α in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.

1371 Objectives To assess the potential contribution of the introduction of diffusion-weighted imaging (DWI) in the PET/MRI protocol for multiple myeloma (MM) assessment. Methods The study includes 24 MM patients (n=15, primary MM; n=9, pre-treated patients). All patients underwent 18F-FDG PET/CT, followed by PET/MRI including DWI. PET/CT and PET/MRI data were assessed and compared based on qualitative and semi-quantitative (SUV) evaluation. DWI findings were matched to respective PET and static MRI (T1w- and T2w-TIRM-sequences) findings. Results In total 138 lesions were detected with at least one method. 71 myeloma-indicative focal lesions were detected with PET/CT. The PET part of PET/MRI revealed 63 of the PET/CT-positive lesions (89%). T1w and T2w-TIRM depicted 128 MM lesions, 61 resembled PET/CT findings (61/71; 86%) and 54 matched respective foci in PET/MRI (54/63; 86%). 9 additional lesions were seen in the PET part but not in the MRI part of PET/MRI. Static MRI-sequences demonstrated 67 PET-negative lesions, 63 of which (94%) were seen in patients that had already undergone therapy. DWI demonstrated a total of 111 focal MM lesions, which were all confirmed in static-MR images. 64 lesions correlated anatomically with the lesions that were also visible in PET/CT, while 47 where DWI-positive and PET/CT-negative. DWI failed to depict 20 lesions detected by static MRI-sequences. Conclusions In our study the use of DWI as part of the PET/MRI protocol did not add significant additional information in addition to well-established T1w/T2w-TIRM sequences in this malignancy. However, the results should be confirmed in larger studies.

Aim of this prospective study was to assess the sensitivity of positron emission tomography (PET) and diffusion-weighted imaging (DWI) in detecting multiple myeloma (MM) lesions, using the well-established morphologic modalities magnetic resonance imaging (MRI) and computed tomography (CT) as the standard of reference (RS). The study included 24 MM patients (15 newly diagnosed, 9 pre-treated). All underwent (18)F-FDG PET/CT and wholebody DWI. The findings in PET and DWI were compared to matching imaging findings in combined non-enhanced T1w, fat-saturated T2w (TIRM)- MRI, and low-dose CT. Patient-based analysis revealed that 15/24 patients (10 primary MM, 5 pre-treated) had myeloma lesions according to our RS. PET was positive in 13/24 patients (11 primary MM, 2 pre-treated) and DWI in 18/24 patients (12 primary MM, 6 pre-treated). Lesion-based analysis demonstrated 128 MM lesions, of which PET depicted 60/128 lesions (sensitivity 47%), while DWI depicted 99/128 lesions (sensitivity 77%). Further analysis including only the 15 untreated MM patients revealed a sensitivity of 90% for both PET and DWI and an overall concordance of PET and DWI of 72%. In conclusion, DWI was more sensitive than (18)F-FDG PET in detecting myeloma lesions in a mixed population of primary and pre-treated MM patients. However, (18)F-FDG PET and DWI demonstrated equivalent sensitivities in the sub-population of primary, untreated MM patients. This higher sensitivity of DWI in pre-treated patients may be due to the fact that (18)F-FDG PET becomes negative earlier in the course of treatment in contrary to MRI, in which already treated lesions can remain visible.

Background Among all hereditary cancer syndromes MEN Type 1 and 2 are characterized by the concurrent but independent appearance of benign as well as malignant tumours. Neoplasias of parathyroid glands, pancreas, pituitary gland as well as neuroendocrine tumours of the stomach and intestinal wall are typical for MEN 1. Medullary thyroid carcinomas together with parathyroid adenomas and phaeochromocytomas are hallmarks of MEN 2. This presentation gives an overview about the multitude of imaging techniques that are inevitable for diagnostics and long-term follow up in MEN patients beyond molecular genetic and laboratory methods. Methods

Methods 55 Patients diagnosed according to the International Myeloma Working Group criteria (2003) were referred to consecutive imaging diagnostics including 18F-FDG PET/CT, T1-weighted and short-tau inversion recovery (STIR) whole-body MRI (WB-MRI) as well as diffusion weighted MRI (DWI). Images were reviewed and matched on a lesion-by-lesion basis for the location and number of focal osseous MM lesions by two radiologists and one nuclear medicine physician, grading the conspicuity of each lesion in CT, T1w, T2 STIR, DWI and ADC-Map separately. PET/CT data were compared based on qualitative and semi-quantitative (SUV) evaluation. A scoring system was used, with a certainty score as the reference for each lesion resulting from an evaluation considering all imaging modalities simultaneously. The analysis was carried out without knowledge of the previous treatment or the stage of disease. Results In static MRI and DWI different infiltration patterns were observed and PET/CT revealed comparable patterns of tracer uptake: negative, focal, diffuse and mixed. MRI including DWI demonstrates both active as well as inactive MM lesions and displays numerous additional PET-negative lesions.

Ziele: Die Behandlungsmöglichkeiten für Patienten mit fortgeschrittenem HCC sind in der Regel limitiert. Ein neuer Behandlungsansatz könnte die Schwerionentherapie mit Kohlenstoffionen sein, die sich durch ein invertiertes Dosisprofil sowie einer hohen lokalen Dosisapplikation im sog. Bragg-peak bei gleichzeitiger Schonung des Normalgewebes auszeichnen. Das Therapieansprechen nach Schwerionenbehandlung mithilfe bildgebender Verfahren wurde bislang nicht beschrieben. Ziel der Studie war es, die diagnostische Wertigkeit der DWI in Kombination mit DECT im Hinblick auf ein Therapieansprechen nach Schwerionentherapie zu evaluieren. Methode: Sieben Patienten mit fortgeschrittenem HCC wurden nach initialer Baseline Untersuchung im Zeitraum 2011 und 2012 mittels MRT (inkl. DWI-Sequenzen) und DECT des Abdomens verlaufskontrolliert. Tumorgröße, Tumordichte (HU) sowie Apparent Diffusion Coefficient (ADC) Werte wurden von zwei Radiologen ausgewertet. Hierbei wurden die HCC-Läsionen auf der T1-post-KM volumetriert und die CT und DWI-Daten hierauf registriert. Partialvolumen- sowie Regressionsanalysen der korrelierten Daten wurden durchgeführt, um Veränderungen dieser Parameter im Verlauf zu beurteilen. Ergebnis: In allen Patienten konnte nach Schwerionentherapie eine Reduzierung der Tumorgröße beobachtet werden. Erste Ergebnisse zeigten eine inverse Korrelation von Dichte-Reduzierung in der DECT und ADC-Anstieg in der DWI nach Schwerionentherapie (1. Verlaufskontrolle nach vier Wochen) als Zeichen des Therapieansprechens. Zwölf Wochen nach Therapie wurde ein Rückgang der ADC- und eine Erhöhung der CT-Dichtewerte, am ehesten bedingt durch Reorganisation des Gewebes, beobachtet. Schlussfolgerung: Die Diffusions-gewichtete Bildgebung in Kombination mit der Dual-Energy CT ist ein vielversprechender Ansatz im Therapiemonitoring nach Schwerionentherapie bei HCC-Patienten. Eine parallele und insbesondere reproduzierbare Auswertung kann hierbei durch Registrierung der DWI- und CT-Daten auf die T1-post-KM erreicht werden.

UNLABELLED:The clinical implementation of whole body diffusion weighted imaging (WB-DWI) for tumor-detection, -characterization and therapy monitoring is well underway. The method is fast, robust and combined with its wide availability on modern MRI scanners, it has a vast potential clinical impact. Owing to the high tumor to background contrast, its main application areas are simple detection of tumor suspicious lesions (primary tumor, recurrence, and metastasis), tumor grading and therapy monitoring.WB-DWI has a strong diagnostic potential regarding the evaluation of bone marrow and its diseases and as thus, tumor detection and therapy monitoring of bone metastasis is of particular interest. The assessment of a lymphatic tumor spreading is constricted. One of the major hurdles that still hamper the wide clinical application of WB-DWI is a lack of standardization of measurement parameters that limit the comparability. of current research results.KEY POINTS:Owing to the high tumor to background contrast WB-DWI allows fast assessment of tumor distribution and total tumor burden. WB-DWI allows therapy monitoring. WB-DWI is widely available.

Ziele: Das Ziel der Studie bestand in einem Vergleich des diagnostischen Wertes der Ganzkörper-Diffusionsbildgebung (GK-DWI) und der FDG-PET-CT zur Erkennung von myelomassoziierten Läsionen. Methode: 15 Patienten mit unbehandeltem Multiplen Myelom (Durie Salmon III) wurden zwischen 2011 und 2012 an zwei aufeinander folgenden Tagen mittels MRT einschließlich DWI und FDG-PET/CT des ganzen Körpers untersucht. Die Lokalisation und die Zahl myelomassoziierter knöcherner Läsionen in der GK-DWI und in der FDG/PET-CT wurden retrospektiv von zwei Radiologen und einem Nuklearmediziner evaluiert. DWI-Läsionen, die auf mindestens 3 Schichten detektierbar waren, wurden als positiv bewertet. Die Referenzmethode stellten T1w, T2w sowie CT dar. Ergebnis: 279 diffuse und fokale Läsionen wurden mittels GK-DWI detektiert, 260 korrelierten in der T1w, der T2w und in der CT (93,18%), davon wurden 41 als diffuse und 219 als fokale Läsionen eingestuft. Die 19 verbleibenden Läsionen (ausschließlich fokal) wurden als falsch positive betrachtet. 165 von den 260 sicheren Läsionen waren in der FDG-PET/CT positiv (63,46%). In der FDG-PET/CT wurden keine falsch positiven Läsionen detektiert. Insgesamt ist der Unterschied zwischen DWI und FDG-PET/CT bezüglich der diagnostischen Effektivität statistisch signifikant (P<0,001), basierend auf T1w, T2w und CT. Schlussfolgerung: Die Ganzkörper-Diffusionsbildgebung ist ein wertvolles Instrument der klinischen Routine, weil durch den hohen Tumor-zu-Normalgewebe-Kontrast Regionen erhöhter Zellularität gut zu erkennen und ein Gesamtüberblick über die Tumorausbreitung und -verteilung schnell gewonnen werden kann. Zudem erlaubt die GK-DWI Therapie-Monitoring. Auch Verlaufsuntersuchungen können ohne die Anwendung ionisierender Strahlung durchgeführt werden. Die Ganzkörper-Diffusionsbildgebung hat damit aufgrund ihrer Verfügbarkeit und Kosteneffizienz im Verleich zur FDG-PET/CT ein signifikantes Potential in der Erkennung myelomassoziierter ossärer Läsionen (DWI>CT>FDG-PET/CT).

OBJECTIVE:The aim of this study was to prove, whether the intracutaneous skin closure with self made fishing line suture is equivalent to commercial sutures.DESIGN:It was a randomised blinded animal study.SETTING:The study was performed in December 2002 at the Muhimbili University College of Health Sciences in Dar-es-salaam.SUBJECTS:Both German surgeons from Mannheim, and Tanzanian surgeons from Dar es salaam operated on nine one year old Tanzanian domestic sheep.INTERVENTIONS:108 standardised cutaneous wounds on the backs of the animals were closed by intracutaneous sutures either with self produced fishing line suture or a commercial nylon suture (Ethilon).MAIN OUTCOME MEASURES:The clinical and histological outcomes, as well as the costs of this self-made fishing line suture, with a commercial nylon thread were evaluated and compared.RESULTS:There are no significant differences between the two sutures in histological or clinical findings, or in the reported ease of use by the surgeons. The cost of a self-produced atraumatic thread is US$ 0.12, less than one-twentieth of the cost of the commercial thread.CONCLUSION:Self-made fishing nylon suture has characteristics and properties in sheep skin wounds comparable to commercial nylon suture. The advantage of the commercial thread is the guaranteed quality assurance. It is discussed whether this quality assurance justifies the large price difference, and whether the self-produced thread should be recommended to surgeons in countries where the costs of surgical material often remains an obstacle for life saving operations.

Die Diffusions-Tensor-Bildgebung ("diffusion tensor imaging", DTI) erlaubt einen In-vivo-Einblick in die Mikroarchitektur des Gehirns und damit die Darstellung einzelner Nervenbahnen. Nach einer Einführung in die Technik werden Möglichkeiten zur Optimierung diskutiert. Weiter folgt ein Überblick über den Stand der Forschung im Zusammenhang mit der Alzheimer-Erkrankung.