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In mammalian cells, AU-rich elements (AREs) are well known regulatory sequences located in the 3' untranslated region (UTR) of many short-lived mRNAs. AREs cause mRNAs to be degraded rapidly and thereby suppress gene expression at the posttranscriptional level. Based on the number of AUUUA pentamers, their proximity, and surrounding AU-rich regions, we generated an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. By analyzing the AREScore distribution in the transcriptomes of 14 metazoan species, we provide evidence that AREs were selected for in several vertebrates and Drosophila melanogaster. We then measured mRNA expression levels genome-wide to address the importance of AREs in SL2 cells derived from D. melanogaster hemocytes. Tis11, a zinc finger RNA-binding protein homologous to mammalian tristetraprolin, was found to target ARE-containing reporter mRNAs for rapid degradation in SL2 cells. Drosophila mRNAs whose expression is elevated upon knock down of Tis11 were found to have higher AREScores. Moreover high AREScores correlate with reduced mRNA expression levels on a genome-wide scale. The precise measurement of degradation rates for 26 Drosophila mRNAs revealed that the AREScore is a very good predictor of short-lived mRNAs. Taken together, this study introduces AREScore as a simple tool to identify ARE-containing mRNAs and provides compelling evidence that AREs are widespread regulatory elements in Drosophila.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN -amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN -amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN -amplified tumors.

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically. Competing Interest Statement The authors have declared no competing interest.

PurposeAccording to the updated WHO classification of gliomas with its emphasis on molecular parameters, tumours with an IDH-wildtype status have a dismal prognosis. To ensure timely adjustment of treatment, demand for non-invasive prediction methods is high. 18F-FET PET has been shown to be an important diagnostic tool for glioma management. The aim of this study was to assess the value of dynamic 18F-FET PET for the non-invasive prediction of the IDH-mutation status.MethodsNewly diagnosed WHO grade II–IV glioma patients with MRI and dynamic 18F-FET PET were included. The 18F-FET PET parameters mean and maximal tumour-to-background ratio (TBRmean, TBRmax) and minimal time-to-peak (TTPmin) were evaluated. The diagnostic power for the prediction of the IDH genotype (positive/negative predictive value) was tested in the overall study group and in the subgroup of non-contrast enhancing gliomas.ResultsThree hundred forty-one patients were evaluated. Molecular analyses revealed 178 IDH-mutant and 163 IDH-wildtype tumours. Overall, 270/341 gliomas were classified as 18F-FET-positive (TBRmax > 1.6), 90.2% of the IDH-wildtype and 69.1% of IDH-mutant gliomas. Median TBRmax was significantly higher in IDH-wildtype compared with IDH-mutant gliomas (2.9 vs. 2.3, p < 0.001); however, ROC-analyses revealed no reliable cutoff due to a high overlap (range 1.0–7.1 vs. 1.1–7.9). Dynamic analysis revealed a significantly shorter TTPmin in IDH-wildtype gliomas; using TTPmin ≤ 12.5 min as indicator for IDH-wildtype gliomas, a positive predictive value of 87% was reached (negative predictive value 72%, AUC = 0.796, p ≤ 0.001). A total of 161/341 gliomas did not show contrast enhancement on MRI; even within this subgroup, TTPmin ≤ 12.5 min remained a good predictor of IDH-wildtype glioma (positive predictive value 83%, negative predictive value 90%; AUC = 0.868, p < 0.001).ConclusionA short TTPmin in dynamic 18F-FET PET serves as good predictor of highly aggressive IDH-wildtype status in gliomas. In particular, a high diagnostic power was observed in the subgroup of non-contrast enhancing gliomas, which helps to identify patients with worse prognosis.

Abstract BACKGROUND: Prognosis and treatment of cystic craniopharyngiomas are poorly defined. OBJECTIVE: To analyze progression-free survival (PFS) and safety profile of cystic craniopharyngiomas undergoing resection or minimally invasive drainage procedures. We compared further outcome measurements for cystic and solid tumors undergoing resection to elucidate the impact of the initial tumor composition on both PFS and the toxicity profile. METHODS: All patients with craniopharyngiomas consecutively treated between 1999 and 2014 were included. A treatment decision in favor of microsurgery or stereotactic treatment was made interdisciplinarily. For stereotactic drainage, a catheter was implanted, allowing both permanent upstream (into ventricular spaces) and downstream (into prepontine cistern) drainage. Study endpoints were tumor progression, functional outcome, and treatment toxicity. Functional endocrinological and visual outcome analyses referred to data obtained preoperatively and 6 weeks after treatment. The Kaplan-Meier method was used for survival analysis. Prognostic factors were obtained from proportional hazard models. RESULTS: Seventy-nine patients were included. The distribution of clinical and tumor-related data was well balanced among patients with solid (n = 35) and cystic (n = 44) tumors and those undergoing microsurgical or stereotactic treatment. Cystic tumors had shorter PFS (5-year PFS: 53.6% vs 66.8%, P = .10) and needed significantly more therapeutic interventions, which was independent of the initial treatment mode. The endocrinological deterioration rate was high for both solid and cystic tumors after microsurgery (59.4% and 85.7%, respectively), whereas it was significantly lower for cystic tumors undergoing stereotactic treatment (23.1%, P < .001). CONCLUSION: Stereotactic bidirectional drainage of cystic craniopharyngiomas is effective and provides a better endocrinological outcome than conventional microsurgery.

Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

Background In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10–12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. Methods All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm 3 ) was subjected to detailed molecular analysis ( MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). Results 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. Conclusions Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment.

APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.

Glioblastoma multiforme continues to be a devastating disease despite modest improvements in survival achieved at present, and there is an urgent need for innovative treatment concepts. Five-aminolevulinic acid (ALA) is a drug which induces protoporphyrin IX accumulation in malignant gliomas and has been explored for fluorescence-guided resections of these tumors. ALA is also under investigation as a photosensitizer. We report a case of a patient with prior left frontal glioblastoma multiforme treated by surgery, radiation and chemotherapy, who developed a remote lesion in the left insula, which was refractory to secondary treatments. In a compassionate use setting she was treated by oral application of ALA (20 mg/kg bodyweight), and stereotactic phototherapy achieved by positioning four laser diffusors using 3-dimensional irradiation planning, and a 633 nm diode laser. The lesion disappeared 24 h after therapy. Circumferential contrast enhancement was observed at 72 h, which disappeared in the course of subsequential months. Edema resolved completely. The patient is still free of recurrence 56 months after treatment, demonstrating an impressive and long-lasting response to this novel mode of therapy.

The aim of the current prospective study was to analyse the validity of MRI based diagnosis of brainstem gliomas which was verified by stereotactic biopsy and follow-up evaluation as well as to assess prognostic factors and risk profile.