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.
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.
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
Radiolabelled somatostatin analogues detect neuroendocrine tumours (NETs), but may reveal other tumour types. We examined the prevalence of possible meningioma in patients with known or suspected NETs imaged with Ga-DOTATATE PET-computed tomography (CT) on the basis of central nervous system uptake and compared with findings on magnetic resonance and contrast-enhanced CT imaging.Retrospective imaging reports from 313 patients who had undergone Ga-DOTATATE PET imaging for primary or repeat NET staging were searched to identify suspected meningiomas on PET. Images were then compared with findings on subsequent complementary MRI or contrast-enhanced CT scanning (performed within mean±112 days of PET-CT) if available.Of 313 patients, 22 had regions of uptake suggestive of meningioma. MRI was available for 12 patients and contrast-enhanced CT was available for one patient. Of these, one patient with known von Hippel-Lindau syndrome had probable cerebellar NET metastasis. Six patient scans indicated lesions consistent with PET. Two of these reported initially did not comment on meningioma. No obvious lesion was found in the remaining six patients; however, five showed a possible correlation to venous structures. The mean maximum standardized uptake value±SEM for lesions in all 21 probable meningioma patients was 4.90±0.45.Ga-DOTATATE is a sensitive marker of probable meningioma and may identify small lesions not reported on subsequent MRI. Lesions clearly observed on PET were identified on review in half of patients where complementary MR or CT imaging was available. Haemangioblastoma and metastatic NETs may have focal peripheral uptake similar to meningioma on Ga-DOTATATE PET and should be considered in the differential.
The reversible cerebral vasoconstriction syndrome (RCVS) is characterised by thunderclap headache and multifocal vasoconstriction of cerebral arteries on angiography. It is often drug induced, but it can occur postpartum, and as a result of a number of other precipitants. To make the diagnosis, it is necessary to exclude other causes of severe headache (such as aneurysmal subarachnoid haemorrhage, carotid dissection and primary angiitis of the central nervous system). However, it is also important to show that the vasoconstriction has resolved with repeat angiography at the 3-month stage. Here we report two cases of RCVS in association with venlafaxine and the urinary antiseptic, methenamine. Serotonin–norepinephrine reuptake inhibitors have recently been reported as a possible precipitant, but this is the first report to implicate methenamine. Although RCVS is relatively uncommon, it should be considered in the differential of those presenting with thunderclap headache.
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.
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