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In recent years, the fabrication of novel building blocks for quantum computation- and spintronics devices gained significant attention. The ultimate goal in terms of miniaturization is the creation of single-atom functional elements. Practically, quantum point contacts are frequently used as model systems to study the fundamental electronic transport properties of such mesoscopic systems. A quantum point contact is characterised by a narrow constriction coupling two larger electron reservoirs. In the absence of a magnetic field, the conductance of these quantum point contacts is quantised in multiples of 2e²/h, the so-called conductance quantum (G0). However, in the presence of magnetic fields the increased spin-degeneracy often gives rise to a deviation from the idealized behaviour and therefore leads to a change in the characteristic conductance of the quantum point contact. Herein, we illustrate the complex magnetotransport characteristics in quantum point contacts and magnetic heterojunctions. The theoretical framework and experimental concepts are discussed briefly together with the experimental results as well as potential applications. [ABSTRACT FROM AUTHOR]

A new species of frogfish, Antennarius monodi sp. nov., is described from the Upper Miocene (Messinian) of Raz-el-Aïn, near Oran, north-east Algeria. The type and only specimen of this taxon is the first articulated skeleton belonging to the family Antennariidae ever recorded as a fossil. The morphological and meristic characters observed support the inclusion of this species in the Antennarius ocellatus group, where it shares several features with the extant Antennarius senegalensis. Morphological features, sedimentary characters and faunal association concur to suggest that A. monodi sp. nov. possibly was a tropical, continental species that lived on muddy bottoms and turbid waters at depths less than 90–100 m. From a biogeographic point of view, the presence of an antennariid closely related to A. senegalensis in the Late Miocene of the Mediterranean suggests that this area had strong biotic relationships with the eastern tropical Atlantic at that time. The integrative analysis of phylogenetic interrelationships and fossil record of the entire order Lophiiformes reveals that all the lophiiform lineages were already in existence in the Eocene. Moreover, the existence of a derived species of the genus Antennarius in the Late Miocene at last fills a large gap that exists in the fossil record of the Teleostei, suggesting that the modern antennariid body plan originated well before that period. [ABSTRACT FROM AUTHOR]

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long‐term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work‐up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. [ABSTRACT FROM AUTHOR]

Aeolianite successions of low-gradient continental margins commonly show complex records of coastal dune deposition linked to a wide range of sea-level positions and climatic periods of the middle and late Pleistocene, recording both regional and broader-scale drivers of sediment production, coastal dune development and landform preservation. To better characterise the general pattern of sedimentation that occurs over Quaternary glacial–interglacial cycles on low-gradient, temperate carbonate continental shelves we examine the morphology, stratigraphy and age of aeolianite deposits in the Perth region, Western Australia. This includes an analysis of well-defined drowned coastal landforms preserved on the adjacent shelf. New and previously published optical ages provide a preliminary timeframe for the deposition of aeolianite in the Perth region and on Rottnest Island, 17 km offshore. An extensive aeolianite ridge near Perth, representing a former barrier, has Optically Stimulated Luminesence (OSL) ages that range from 120 ± 12 to 103 ± 10 ka (MIS 5e–5a in the context of associated age uncertainties). OSL ages for an exposure in the same ridge 2.5 km inland, record the onlap of much older aeolianite, OSL age 415 ± 70 ka, by shell-rich estuarine beds, OSL age 290 ± 30 ka. A further 5.5 km inland from the coast, two thick aeolianite units, separated by a well-developed palaeosol, have stratigraphically consistent OSL ages of 310 ± 30 and 155 ± 20 ka. In contrast, aeolianite units that form the northern coast of Rottnest Island have OSL ages of 77 ± 12 ka and 27 ± 5 ka. The new OSL ages and previously reported TL and U/Th ages indicate that the bulk of the island comprises dunes deposited around the end of the Last Interglacial sensu lato (MIS 5a–4) and during the Last Glacial (MIS 4–2), accumulating over a Last Interglacial coral reef and basal calcarenite. Drowned barrier and dune landforms preserved on the adjacent continental shelf reveal that barriers were formed during periods of intermediate sea level (e.g. MIS 3) and significant dune mobility occurred when the shelf was subaerially exposed. The pattern of shelf sedimentation discernible in the Perth region – large-scale coastal carbonate dune deposition during periods of high and intermediate sea level and reactivation during glacial lowstands – is largely consistent with published stratigraphic and age data for large-scale aeolianite deposits on other low-gradient carbonate shelves. Based on these data, a general model is proposed for the cycle of Quaternary sedimentation and landform evolution that occurs on these shelves, which are dynamic sedimentary environments with coastal landforms and sedimentary successions that are very sensitive to erosion and sediment reworking. [ABSTRACT FROM AUTHOR]

New analytical techniques have opened up the possibility of addressing rates of soil processes quantitatively. Here, we present the results of an investigation into the use of single-grain optically stimulated luminescence (OSL) dating to derive rates of soil mixing in the top 50 cm of soil profiles from two toposequences situated in the Werrikimbe National Park in Australia. Of 500 single grains analysed from each sampled depth increment, less than 25% provided a finite age, with the rest of the grains either non-responsive or dose-saturated. This proportion of finite-age grains tended to decrease with soil depth. Median ages of quartz grains increased down the soil profile, with topsoil ages of up to 500 years and subsoil ages of up to 5000 years. Few 'younger' grains were found deeper in the profile and few 'older' grains near the soil surface. These trends suggest that pedoturbation is resulting in vertical transport of grains through the profile, but that there is a distribution of transport distances, with a poor probability of large transport distances from surface to subsoil or vice versa compared with a more frequent movement of grains to and from the surface in the uppermost 10-35 cm. The calculation of a single age for each soil horizon was unachievable as each horizon contained a heterogeneous mixture of grains with varying histories of transport to and from the soil surface. Soil mixing was confirmed along both toposequences studied. However, the occurrence of minor mixing rates did not lead to a homogenization of the topsoil and adjacent horizons. We postulated that mixing velocities were mostly related to flora at our study site. Vertical soil mixing rates of 0.5 and 0.2 mm year−1 were calculated from the distribution of finite single-grain ages. [ABSTRACT FROM AUTHOR]

Background: Cancer research has made great progress in the recent years. With the increasing number of options in diagnosis and therapy the implementation of tumorboards (TUBs) has become standard procedure in the treatment of cancer patients. Adherence tests on tumor board decisions are intended to enable quality assurance and enhancement for work in tumor boards in order to continuously optimize treatment options for cancer patients.Methods: Subject of this study was the adherence of the recommendations made in three of 14 tumorboards, which take place weekly in the Center for Integrated Oncology (CIO) at the University Hospital Bonn. In total, therapy recommendations of 3815 patient cases were checked on their implementation. A classification into four groups has been made according to the degree of implementation. A second classification followed regarding the reasons for differences between the recommendation and the therapy which the patient actually received.Results: The study showed that 80.1% of all recommendations in the three TUBs were implemented. 8.3% of all recommendations showed a deviance. Most important reasons for the deviances were patient wish (36.5%), patient death (26%) and doctoral decision, due to the patient's comorbidities or side effects of the treatment (24.1%).Interestingly, deviance in all three tumor boards in total significantly decreased over time.Conclusions: Aim of the study was to clarify the use of tumor boards and find approaches to make them more efficient. Based on the results efficiency might be optimized by increased consideration of patients` preferences, improved presentation of patient-related data, more detailed documentation and further structuring of the tumor board meetings. [ABSTRACT FROM AUTHOR]

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination. [ABSTRACT FROM AUTHOR]

Low-temperature electronic transport measurements with high energy resolution require both effective low-pass filtering of high-frequency input noise and an optimized thermalization of the electronic system of the experiment. In recent years, elaborate filter designs have been developed for cryogenic low-level measurements, driven by the growing interest in fundamental quantum-physical phenomena at energy scales corresponding to temperatures in the few millikelvin regime. However, a single filter concept is often insufficient to thermalize the electronic system to the cryogenic bath and eliminate spurious high frequency noise. Moreover, the available concepts often provide inadequate filtering to operate at temperatures below 10 mK, which are routinely available now in dilution cryogenic systems. Herein we provide a comprehensive analysis of commonly used filter types, introduce a novel compact filter type based on ferrite compounds optimized for the frequency range above 20 GHz, and develop an improved filtering scheme providing adaptable broad-band low-pass characteristic for cryogenic low-level and quantum measurement applications at temperatures down to few millikelvin. [ABSTRACT FROM AUTHOR]

Aim Pilocytic astrocytomas represent the most common paediatric tumours of the central nervous system. Dissemination through the ventricular system occurs rarely in patients with pilocytic astrocytomas; however, it is more common in infants with diencephalic tumours, and is associated with a poor outcome. Despite histological similarities with classic pilocytic astrocytomas, it is still unclear whether disseminated pilocytic astrocytomas may have specific molecular features. Methods Seventeen disseminated pilocytic astrocytomas were investigated using the molecular inversion probe array and screened for the presence of gene fusions ( KIAA1549-BRAF) and mutations ( BRAF, RAS and FGFR1). Results Along with evidence of a constitutive MAPK activation in all cases, the molecular inversion probe array, fluorescence in situ hybridization analysis and mutational study revealed KIAA1549-BRAF fusions in 66% and BRAFV600E mutations in 5% of cases. No KRAS, HRAS, NRAS or FGFR1 mutations were found. Conclusions disseminated pilocytic astrocytomas showed genetic features similar to classic pilocytic astrocytoma, including a similar incidence of KIAA1549-BRAF fusions, BRAF mutations and a stable genetic profile. Given common activation of the MAPK pathway, the use of specific inhibitors can be hypothesized for the treatment of disseminated pilocytic astrocytomas, along with standard chemo- and/or radiotherapy. [ABSTRACT FROM AUTHOR]

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial. [ABSTRACT FROM AUTHOR]

Background This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. Patients and methods Histology, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan–Meier method. Prognostic factors were assessed with proportional hazard models. Results Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). Conclusions The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy. [ABSTRACT FROM PUBLISHER]

Background:High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation.Methods:Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG.Results:Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92±0.02 vs 2.03±0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019).Conclusion:High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location. [ABSTRACT FROM AUTHOR]

M. Gessi, J. Hammes, L. Lauriola, E. Dörner, J. Kirfel, G. Kristiansen, A. zur Muehlen, D. Denkhaus, A. Waha and T. Pietsch (2013) Neuropathology and Applied Neurobiology 39, 417-425 GNA11 and N-RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system Aim: Primary melanocytic tumours are uncommon neoplasms of the central nervous system. Although similarities with uveal melanomas have been hypothesized, data on their molecular features are limited. Methods: In this study, we investigated the mutational status of BRAFV600E, KIT, GNAQ, GNA11, N-RAS and H-RAS in a series of 19 primary melanocytic tumours of the central nervous system (CNS). Results: We identified six cases harbouring mutations in the hotspot codon 209 of the GNAQ gene and two cases with mutations in the hotspot codon 209 of the GNA11 gene. Two mutations in codon 61 of N-RAS were also found. In the single strand conformation polymorphism (SSCP) analysis, no shifts corresponding to BRAFV600E mutations or suggesting activating mutations in the KIT gene were observed. Conclusions: In primary melanocytic tumours of the CNS, GNA11 and N-RAS mutations represent a mechanism of MAPK pathway activation alternative to the common GNAQ mutations. On the other hand, BRAFV600E mutations and activating KIT mutations seem to be absent or very rare in these tumours. [ABSTRACT FROM AUTHOR]

We report the observation of strong resonances at zero bias in the differential conductance through Al-C60-Al junctions with tunable electrode distance, measured above T = 10 K. The conductance value at resonance ranges from a few percent up to eighty percent of the quantum of conductance. The resonances may disappear or reoccur completely and discontinuously upon very small changes of the electrode distance. However, once they are formed they are very robust with respect to changes of the electrode distance. We discuss similarities and differences to the common theories of the Kondo screening of a spontaneous spin polarization of the C60 molecule. We deduce Kondo temperatures in the range from 35 to 160 K and demonstrate that the temperature dependence is in agreement with the scaling behavior of the Kondo effect in the temperature range of our experiment. [ABSTRACT FROM AUTHOR]

Background:Tumours are responsive to temozolomide (TMZ) if they are deficient in O6-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient.Methods:The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1.Results:Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC50=1.7 μM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O6-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry).Conclusion:A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient. [ABSTRACT FROM AUTHOR]

Background: There is significant inter-observer variation amongst the neuro-pathologists in the typing, subtyping, and grading of glial neoplasms for diagnosis. Centralized pathology review has been proposed to minimize this inter-observer variation and is now almost mandatory for accrual into multicentric trials. We sought to assess the concordance between neuro-pathologists on histopathological diagnosis of glioblastoma. Materials and Methods: Comparison of local, institutional, and central neuro-oncopathology reporting in a cohort of 34 patients with newly diagnosed supratentorial glioblastoma accrued consecutively at a tertiary-care institution on a prospective trial testing the addition of a new agent to standard chemo-radiation regimen. Results: Concordance was sub-optimal between local histological diagnosis and central review, fair between local diagnosis and institutional review, and good between institutional and central review, with respect to histological typing/subtyping. Twelve (39%) of 31 patients with local histological diagnosis had identical tumor type, subtype and grade on central review. Overall agreement was modestly better (52%) between local diagnosis and institutional review. In contrast, 28 (83%) of 34 patients had completely concordant histopathologic diagnosis between institutional and central review. The inter-observer reliability test showed poor agreement between local and central review (kappa statistic=0.12, 95% confidence interval (CI): -0.03-0.32, P=0.043), but moderate agreement between institutional and central review (kappa statistic=0.51, 95%CI: 0.17-0.84, P=0.00003). Agreement between local diagnosis and institutional review was fair. Conclusions: There exists significant inter-observer variation regarding histopathological diagnosis of glioblastoma with significant implications for clinical research and practice. There is a need for more objective, quantitative, robust, and reproducible criteria for better subtyping for accurate diagnosis. [ABSTRACT FROM AUTHOR]

M. Gessi, A. zur Muehlen, L. Lauriola, M. P. Gardiman, F. Giangaspero and T. Pietsch (2011) Neuropathology and Applied Neurobiology 406-413 ? The primitive neuroectodermal tumours of central nervous system (CNS?PNET) are a heterogeneous group of neoplasms, occurring in the CNS and composed of undifferentiated or poorly differentiated neuroepithelial cells which may display divergent differentiation along neuronal, astrocytic and ependymal lines. The WHO classification includes in this group of tumours also ependymoblastomas and medulloepitheliomas. Several groups have reported examples of CNS?PNET with combined histological features of ependymoblastoma and neuroblastoma, defined as 'embryonal tumour with abundant neuropil and true rosettes'. The presence of the amplification of chromosome region 19q13.42, common in both ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes, suggests that they represent a histological spectrum of a single biological entity. We examined 24 cases of ependymoblastoma/embryonal tumour with abundant neuropil and true rosettes (EPBL/ETANTR) for the presence of mutations of TP53 and ??Catenin and for amplification of c?myc/N?myc. The single strand conformation polymorphism?mutational screening did not identify any mutation in exons 5 to 8 of the TP53 gene. However, we found a point mutation affecting codon 34 (GGA?GTA) of ??Catenin gene resulting in a Glycine ? Valine substitution. No cases presented c?myc/N?myc amplification. EPBL/ETANTRs show molecular features different from other CNS?PNET and medulloblastomas. The presence of alterations in the ??Catenin/WNT pathway seems to be noteworthy due to the close relationship between this pathway and miR?520g encoded in chromosome 19q13.42 region amplified in these tumours. [ABSTRACT FROM AUTHOR]

Abstract: The Daly River occupies a mainly undisturbed large catchment in the Australian wet–dry tropics. Concerns about possible increased sediment input to the River from clearing and cropping have motivated this study of fine sediment sources. Using geochemical tracers for both modern sediments and alluvial bench deposits, it is shown that, for the last ~30 years, 89–97% of the fine sediment originates from erosion by gullying and channel change. There is no discernible input of top soil from the cleared land adjacent to the Daly River in the study area. The analysis and OSL dating of the alluvial benches have also provided data on the age of (and inferences about the causes of) bench formation, flood frequency change, sedimentation rate change, and episodes of sand transport. The benches are being destroyed as the channel widens (contributing sediment to the river) and the bed of the Daly appears to be shallowing, both responses to increased overbank flows. The sediment source created by channel widening is almost all the result of hydrologic change, with no discernible role for land use. [Copyright &y& Elsevier]

PURPOSE: To analyse long-term outcome and clinical prognostic factors in medulloblastoma. METHODS: We analysed 280 patients with medulloblastoma (3-18 years) included from 1991 to 1997 in the randomised multicentre trial HIT'91 comparing pre-('sandwich') and postradiation ('maintenance') chemotherapy (median follow-up of survivors for 10 years). RESULTS: In 187 patients with complete staging, overall survival (OS) was higher after maintenance compared to sandwich treatment for M0 (10-year OS 91% and 62%, p=0.001) and M1 patients (10-year OS 70% and 34%, p=0.020). In M2/3 disease, 10-year OS was 42% and 45%. Incomplete staging, metastases, younger age and sandwich chemotherapy were independent adverse risk factors. Twelve percent of all relapses (13 of 107) occurred after more than five years, and 12 patients had secondary neoplasms. CONCLUSIONS: After maintenance therapy, long-term survival was excellent in fully assessable patients with localised medulloblastoma, and favourable for M1 patients. Patients should be followed longer for late relapses and secondary tumours. [ABSTRACT FROM AUTHOR]

Aim: Microsatellite instability (MSI) has been proposed as a possible mechanism in the development of cancer. The aim of the current study was to determine whether MSI is involved in the pathogenesis of paediatric malignant astrocytomas. Methods: We screened a cohort of 126 high-grade astrocytoma samples for MSI using a sensitive and precise method of DNA analysis including a panel of five mononucleotide repeats, in combination with immunohistochemistry for DNA mismatch repair (MMR) proteins. Results: We identified low level of MSI (MSI-L) in four of 126 (3.2%) paediatric malignant astrocytic tumours. To analyse the molecular profile associated with MSI-L positive tumours, we performed immunohistochemistry for protein expression of hMSH6 and p53 as well as mutational analysis of the K- ras gene. In MSI-L paediatric malignant astrocytic tumours we detected retained nuclear expression of hMSH6 protein and strong nuclear accumulation of p53 protein indicating possible mutations of TP53. There was no correlation between K- ras mutational status and frequency of MSI in this patient population. Conclusion: Our results suggest that the MSI-L phenotype is associated with p53 accumulation and/or mutations. However, this represents only a small subgroup of paediatric gliomas with possible distinct biological features, and the deficiencies of DNA MMR genes do not play a main role in the tumourigenesis of the majority of paediatric malignant astrocytomas. [ABSTRACT FROM AUTHOR]

Indurated sand in the Late Quaternary coastal plain succession of northern Moreton Bay was examined in sand-mine pits, drillcores and the eroded bank of an estuarine channel. Samples show that the cements usually coat grains and partially infill interstitial pores. Distinctive cement habits reflect different constituents that are dominantly kaolinite and amorphous organic-rich complexes. Trace-metal concentrations in the cements are lower than previously reported for soils and estuarine sediments in the study region. Optically stimulated luminescence and thermoluminescence ages of these deposits indicate that pedogenic induration occurs over long periods, up to approximately 90 000 years, with only incipient induration evident in deposits 16 000 - 2600 years old. However, the rate of induration is far higher in relatively coarse channel fill, in which mineral and amorphous organic-rich cements have precipitated from shallow groundwater that flowed laterally through the deposit. The degree of induration, therefore, is strongly influenced by the original depositional texture and morphology of deposits, with well-indurated gravely channel fill (76 700 ± 6500 y), at least 2 m thick, sitting adjacent to medium-grained sand probably of dune origin, which contains a 30 cm-thick induration horizon (98 000 ± 9900 y). [ABSTRACT FROM AUTHOR]

In a genome-wide screen using differential methylation hybridization (DMH), we have identified a CpG island within the 5′ region and untranslated first exon of the secretory granule neuroendocrine protein 1 gene (SGNE1/7B2) that showed hypermethylation in medulloblastomas compared to fetal cerebellum. Bisulfite sequencing and combined bisulfite restriction assay were performed to confirm the methylation status of this CpG island in primary medulloblastomas and medulloblastoma cell lines. Hypermethylation was detected in 16/23 (70%) biopsies and 7/8 (87%) medulloblastoma cell lines, but not in non-neoplastic fetal (n=8) cerebellum. Expression of SGNE1 was investigated by semi-quantitative competitive reverse transcription–polymerase chain reaction and found to be significantly downregulated or absent in all, but one primary medulloblastomas and all cell lines compared to fetal cerebellum. After treatment of medulloblastoma cell lines with 5-aza-2′-deoxycytidine, transcription of SGNE1 was restored. No mutation was found in the coding region of SGNE1 by single-strand conformation polymorphism analysis. Reintroduction of SGNE1 into the medulloblastoma cell line D283Med led to a significant growth suppression and reduced colony formation. In summary, we have identified SGNE1 as a novel epigenetically silenced gene in medulloblastomas. Its frequent inactivation, as well as its inhibitory effect on tumor cell proliferation and focus formation strongly argues for a significant role in medulloblastoma development.Oncogene (2007) 26, 5662–5668; doi:10.1038/sj.onc.1210338; published online 5 March 2007 [ABSTRACT FROM AUTHOR]

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered. [ABSTRACT FROM AUTHOR]

Cytogenetic and molecular genetic studies have shown frequent losses on the long arm of chromosome 14 in different types of human gliomas. Using differential methylation hybridization as a genome-wide screening approach to determine DNA methylation patterns in gliomas, we recently identified two DNA fragments in 14q23.1 (CGI-clone ♯396) and 14q32.12 (CGI-clone ♯519) that were differentially methylated between astrocytic gliomas and mixed oligoastrocytomas. To validate this observation, we examined these 14q32.12 locus for methylation in an extended series of 43 astrocytic and oligodendroglial gliomas. All tumours were additionally investigated for loss of heterozygosity (LOH). Microsatellite analysis showed LOH in seven of 28 (25%) oligodendroglial tumours and three of 15 (20%) astrocytic tumours. Seven tumours demonstrated LOH at all informative 14q loci whereas three tumours carried partial deletions defining a commonly deleted region at 14q22.3–q32.1 between the microsatellite markers D14S282 and D14S995. Methylation-specific PCR analysis of the 14q32.12 locus revealed hypermethylation in 12 of 43 gliomas (28%). Hypermethylation was restricted to tumours with oligodendroglial differentiation (12 of 28 tumours, 43%). However, none of the hypermethylated tumours demonstrated LOH on 14q and vice versa. In total, 19 of 28 oligodendroglial tumours (68%) showed either hypermethylation at the 14q32.12 locus or LOH at 14q22.3–q32.2. Taken together, our data lend further support for the location of one or more yet to be identified glioma-associated tumour suppressor gene(s) on 14q. In addition, the restriction of 14q32.12 methylation to oligodendroglial tumours suggests a role for epigenetic DNA modifications in these particular gliomas. [ABSTRACT FROM AUTHOR]

Aims: To compare the suitability of new seminoma markers including transcription factors AP-2γ, OCT3/4 and M2A for detection of metastatic and extragonadal seminomas with the two well-known markers c-KIT and PLAP. Materials and methods: The immunohistochemical distribution of PLAP, c-KIT, M2A, AP-2γ and OCT3/4 was examined in two pineal germinomas, 28 metastatic seminomas and 10 of their testicular primaries. Evaluation of specificity was achieved by additional tissue array studies on 75 malignancies other than germ cell tumours (GCT). Clinical data including serum PLAP were available in 18 patients. Results: Compared with other markers, significantly better staining results were observed with antibodies to M2A and AP-2γ in all seminomatous GCT. In contrast, the staining pattern with antibodies to c-KIT, PLAP and OCT3/4 was variable or absent. The lowest specificity was obtained with c-KIT, which was expressed in a variety of non-GCT. The only M2A+ mesothelioma expressed no other seminoma markers. No correlation between serum PLAP level and tissue PLAP expression was found. Conclusions: M2A and AP-2γ are the most sensitive markers for seminoma metastases or primary extragonadal seminomas. Combination of these markers provides highly specific and clear results for detection of a seminomatous GCT. [ABSTRACT FROM AUTHOR]

A. Koch, A. Waha, W. Hartmann, U. Milde, C. G. Goodyer, N. Sörensen, F. Berthold, B. Digon-Söntgerath, J. Krätzschmar, O. D. Wiestler and T. Pietsch (2004)Neuropathology and Applied Neurobiology, doi: 10.1111/j.1365-2990.2004.00560.xNo evidence for mutations or altered expression of theSuppressor of Fusedgene(SUFU)in primitive neuroectodermal tumoursThe sonic hedgehog (Shh) and the Wnt signalling pathways are involved in the development of medulloblastomas (MBs), the most frequent malignant brain tumours in children. Components of these two developmental and cancer-associated pathways, including (Patched)PTCH,SMOH,adenomatous polyposis coli(APC),β-cateninandAXIN1show somatic mutations in sporadic MBs. In this study we analysedSUFU(human suppressor of fused), which acts as a negative regulator of both the Shh and Wnt signalling pathways and therefore represents a putative tumour suppressor gene, to find out if it is also involved in the pathogenesis of sporadic MBs. We screened 145 primitive neuroectodermal tumours (PNETs) including 90 classic MBs, 42 of the desmoplastic variant and two medullomyoblastomas as well as 11MB cell lines for mutations using single-strand conformational polymorphism (SSCP) and sequencing analysis. 18% of the MBs exhibited allelic losses on chromosome 10q. In contrast to a previous report, in which truncating mutations ofSUFUhave been identified in 9% of MBs, we were not able to identify somatic mutations ofSUFUin our large tumour panel. We uncovered single nucleotide polymorphisms (SNPs) in exon 4, 8, 11 and in intron 2 in theSUFUgene. Expression analysis by competitive reverse transciption-polymerase chain reaction (RT-PCR) revealed no difference inSUFUmRNA levels of both MB subtypes and normal foetal or adult cerebellar tissues. Our results indicate that genetic alterations of theSUFUgene, do not contribute significantly to the molecular pathogenesis of MBs. [ABSTRACT FROM AUTHOR]

Supratentorial primitive neuroectodermal tumours (sPNETs) are malignant central nervous system tumours of childhood which are histologically characterized by poorly differentiated neuroepithelial cells with the capacity for divergent differentiation into glial, neuronal, myogenic or melanotic lines. The histological differential diagnosis between sPNET and glioblastoma multiforme (GBM) may be difficult, particularly as GBMs can sometimes demonstrate a poorly differentiated PNET-like phenotype. To identify molecular genetic markers that may distinguish sPNET and GBM, we investigated 12 cerebral sPNETs and six GBMs from paediatric patients for genetic alterations of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 genes, as well as for allelic loss on chromosome arms l0q and 17p. Mutations of the TP53 tumour suppressor gene were found in one of 12 sPNE% (8%) and two of six GBMs (33 %). None of the sPNETs but two of six GBMs (33%, including one GBM with a TP53 mutation) showed allelic losses on chromosome arm 17p. PTEN mutations were detected in one of 12 sPNET (8%) and one of six GBMs (17%). None of the sPNETs and GBMs carried a homozygous deletion involving the CDKN2A tumour suppressor gene. No amplification of the EGFR, CDK4 or MDM2 proto-oncogenes was detected. Taken together, our results indicate that paediatric GBMs differ from sPNETs by a higher incidence of allelic losses on 17p and TP53 mutations. In addition, the patterns of genetic alterations in sPNETs and paediatric GBMs appear to be distinct from those in cerebellar medulloblastomas and adult GBMs, respectively. [ABSTRACT FROM AUTHOR]

Medulloblastomas (MBs) are malignant primitive neuroectodermal tumours (PNETs) of the cerebellum occurring predominantly in childhood. The association of monosomy of chromosome 22 with MB is controversial. Atypical teratoid/rhabdoid tumours (AT/RTs) of the brain share clinical and histological features with MBs and supratentorial PNETs (sPNETs). In particular, AT/RTs can be misdiagnosed as MBs and sPNETs because AT/RTs frequently contain areas of primitive neuroepithelial cells similar to PNETs. Recently, mutations of the tumour suppressor gene hSNF5/INI1 , located on 22q11.23, have been described in AT/RTs, MBs and sPNETs, with conflicting data on the prevalence of hSNF5/INI1 mutations in the latter entities. Therefore, we screened MBs for point mutations and homozygous deletions of the hSNF5/INI1 tumour suppressor gene. In 90 MBs, no mutations of the hSNF5/INI1 gene were identified. Thus, our study virtually rules out hSNF5/INI1 as a tumour suppressor gene involved in the pathogenesis of medulloblastoma. [ABSTRACT FROM AUTHOR]

Previous reports have demonstrated that expression of insulin-like growth factor 2 (IGF2) is altered in hepatoblastoma. Using RNAase protection analysis (RPA), we examined the gene expression for IGF1, IGF2, IGF1R, M6P/IGF2R, IGFBP-1 and IGFBP-2 in a series of hepatoblastomas with corresponding normal liver from the same individuals. The results show that the expression of the IGF-axis members included in the present study are altered between tumour and normal, and indicate that the IGF-axis may be involved in hepatoblastoma development. [ABSTRACT FROM AUTHOR]

Since the rapid technological progress demands for ever smaller storage units, the emergence of stable magnetic order in nanomaterials down to the single-atom regime has attracted huge scientific attention to date. Electronic transport spectroscopy has been proven to be a versatile tool for the investigation of electronic, magnetic, and mechanical properties of atomic contacts. Here we report a comprehensive experimental study of the magnetoconductance and electronic properties of Pd atomic contacts at low temperature. The analysis of electronic transport (dI/dV) spectra and the magnetoconductance curves yields a diverse behavior of Pd single-atom contacts, which is attributed to different contact configurations. The magnetoconductance shows a nonmonotonous but mostly continuous behavior, comparable to those found in atomic contacts of band ferromagnets. In the dI/dV spectra, frequently, a pronounced zero-bias anomaly (ZBA) as well as an aperiodic and nonsymmetric fluctuation pattern are observed. While the ZBA can be interpreted as a sign of the Kondo effect, suggesting the presence of magnetic impurity, the fluctuations are evaluated in the framework of conductance fluctuations in relation to the magnetoconductance traces and to previous findings in Au atomic contacts. This thorough analysis reveals that the magnetoconductance and transport spectrum of Au atomic contacts can completely be accounted for by conductance fluctuations, while in Pd contacts the presence of local magnetic order is required. [ABSTRACT FROM AUTHOR]