Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas

In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors

Detection of mitochondrial defects by laser fluorimetry

Abstract The mitochondrial function in skeletal muscle biopsies of three patients with chronic progressive external ophthalmoplegia, having deletions of the mitochondrial DNA, was studied by laser-excited fluorescence measurements of NAD(P)H and flavoproteins in saponin-skinned fibers. We detected substantially elevated steady state redox states of the mitochondrial NADsystem in the muscle fibers of these patients. Moreover, the respiratory chain-linked autofluorescence changes in the muscle fibers of these patients were larger in comparison to controls indicating substantial alterations of the mitochondrial content. These results are in line with the presence of elevated numbers of partially respiratory chain inhibited mitochondria in the skeletal muscle of chronic progressive external ophthalmoplegia patients. (Mol Cell Biochem 174: [97][98][99][100] 1997

ASA404, a vascular disrupting agent, as an experimental treatment approach for brain tumors

Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo

Delivering bioactive compounds to fish larvae using microencapsulated diets

15 páginas, 6 figuras, 6 tablas.The efficient delivery of nutrients and hormones has special relevance to the development of rearing technologies for fish larvae and juveniles. The main aim is to find an effective and measurable way to administer them into the body of small aquatic animals. In this study, three different compounds (hormones, amino acids, and vitamins) were incorporated into protein-walled microencapsulated diets. Specifically these microencapsulated diets were examined for (a) the kinetics of incorporation of estradiol in Sparus aurata larvae, (b) absorption and leaching patterns of the free amino acids (FAA), and (c) growth results and tissue incorporation of vitamins in relation to the supplementation of vitamin C in larvae of S. aurata and Solea senegalensis. The efficiency of inclusion was relatively low, but the capsules were able to retain enough of these compounds when immersed in water and to deliver them into the digestive tract of the larvae. There are noticeable differences among the nominal amount of a given substance in the ingredient mixture, the actual amount in the microparticle and the amount delivered in the larval gut. It is therefore necessary to examine carefully whether the ingredient is reaching the digestive tract for achieving suitable conclusions in nutritional studies. These results indicate the applicability of these microencapsulated particles in nutritional studies of small aquatic animals.The Commission for Cultural, Educational and Scientific Exchange between the United States of America and Spain (project 97/156) and the Comisión Interministerial de Ciencia y Tecnología, Spain (CICYT Project AGL2000-0697-C02-01) supported this work.Peer reviewe

Clinical Characteristics and Magnetic Resonance Imaging-Based Prediction of the KLF4(K409Q) Mutation in Meningioma

BACKGROUND: Meningioma is the most common primary brain tumor in adults. In recent years, several non-neurofibromin 2 mutations, i.e., AKT1, SMO, TRAF7, and KLF4 mutations, specific for meningioma have been identified. This study aims to analyze the clinical impact and imaging characteristics of the KLF4(K409Q) mutation in meningioma. METHODS: Clinical, neuropathologic, and imaging data of 170 patients who underwent meningioma resection between 2013 and 2018 were retrospectively collected and tumors were analyzed for the presence of the KLF4(K409Q) mutation. We collected imaging characteristics, performed volumetric analysis of tumor size and peritumoral edema (PTBE), and calculated the edema index (EI, i.e., ratio of PTBE to tumor volume). Receiver operating characteristic curve analysis was performed to identify cut-off EI values to predict the mutational status of KLF4. RESULTS: Eighteen (10.6%) of the meningiomas carried the KLF4(K409Q) mutation; these were significantly associated with a secretory subtype (P < 0.001) and sphenoid wing location (P = 0.029). Smaller tumor size (P = 0.007), an increased PTBE (P = 0.012), and an increased EI (P = 0.001) proved to be significantly associated with the KLF4(K409Q) mutation. In receiver operating characteristic curve analysis, EI predicted the KLF4(K409Q) mutation with an area under the curve of 0.728 (P = 0.0016). CONCLUSIONS: The KLF4(K409Q) mutation is associated with a distinct small tumor subtype, prone to substantial PTBE. EI is a reliable parameter to predict the KLF4(K409Q) mutation in meningioma, thus providing a tool for improvement of pre- and perioperative medical management