Acceleration of electrons in the plasma wakefield of a proton bunch.

High-energy particle accelerators have been crucial in providing a deeper understanding of fundamental particles and the forces that govern their interactions. To increase the energy of the particles or to reduce the size of the accelerator, new acceleration schemes need to be developed. Plasma wakefield acceleration1-5, in which the electrons in a plasma are excited, leading to strong electric fields (so called 'wakefields'), is one such promising acceleration technique. Experiments have shown that an intense laser pulse6-9 or electron bunch10,11 traversing a plasma can drive electric fields of tens of gigavolts per metre and above-well beyond those achieved in conventional radio-frequency accelerators (about 0.1 gigavolt per metre). However, the low stored energy of laser pulses and electron bunches means that multiple acceleration stages are needed to reach very high particle energies5,12. The use of proton bunches is compelling because they have the potential to drive wakefields and to accelerate electrons to high energy in a single acceleration stage13. Long, thin proton bunches can be used because they undergo a process called self-modulation14-16, a particle-plasma interaction that splits the bunch longitudinally into a series of high-density microbunches, which then act resonantly to create large wakefields. The Advanced Wakefield (AWAKE) experiment at CERN17-19 uses high-intensity proton bunches-in which each proton has an energy of 400 gigaelectronvolts, resulting in a total bunch energy of 19 kilojoules-to drive a wakefield in a ten-metre-long plasma. Electron bunches are then injected into this wakefield. Here we present measurements of electrons accelerated up to two gigaelectronvolts at the AWAKE experiment, in a demonstration of proton-driven plasma wakefield acceleration. Measurements were conducted under various plasma conditions and the acceleration was found to be consistent and reliable. The potential for this scheme to produce very high-energy electron bunches in a single accelerating stage20 means that our results are an important step towards the development of future high-energy particle accelerators21,22.

Experimental Observation of Proton Bunch Modulation in a Plasma at Varying Plasma Densities.

We give direct experimental evidence for the observation of the full transverse self-modulation of a long, relativistic proton bunch propagating through a dense plasma. The bunch exits the plasma with a periodic density modulation resulting from radial wakefield effects. We show that the modulation is seeded by a relativistic ionization front created using an intense laser pulse copropagating with the proton bunch. The modulation extends over the length of the proton bunch following the seed point. By varying the plasma density over one order of magnitude, we show that the modulation frequency scales with the expected dependence on the plasma density, i.e., it is equal to the plasma frequency, as expected from theory.

Experimental Observation of Plasma Wakefield Growth Driven by the Seeded Self-Modulation of a Proton Bunch.

We measure the effects of transverse wakefields driven by a relativistic proton bunch in plasma with densities of 2.1×10^{14} and 7.7×10^{14} electrons/cm^{3}. We show that these wakefields periodically defocus the proton bunch itself, consistently with the development of the seeded self-modulation process. We show that the defocusing increases both along the bunch and along the plasma by using time resolved and time-integrated measurements of the proton bunch transverse distribution. We evaluate the transverse wakefield amplitudes and show that they exceed their seed value (<15 MV/m) and reach over 300 MV/m. All these results confirm the development of the seeded self-modulation process, a necessary condition for external injection of low energy and acceleration of electrons to multi-GeV energy levels.

Proton-driven plasma wakefield acceleration in AWAKE.

In this article, we briefly summarize the experiments performed during the first run of the Advanced Wakefield Experiment, AWAKE, at CERN (European Organization for Nuclear Research). The final goal of AWAKE Run 1 (2013-2018) was to demonstrate that 10-20 MeV electrons can be accelerated to GeV energies in a plasma wakefield driven by a highly relativistic self-modulated proton bunch. We describe the experiment, outline the measurement concept and present first results. Last, we outline our plans for the future. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

At-vessel mortality of skates (Rajidae) taken in coastal fisheries and evidence of longer-term survival.

Data on the vigour and at-vessel mortality (AVM) of 6798 skates (comprising Raja clavata n = 6295; R. brachyura n = 208; R. undulata n = 185, R. montagui n = 98 and R. microocellata n = 12) captured by commercial fishing vessels in the inshore waters of the southern North Sea and English Channel were recorded. AVM in longline fisheries averaged 0·44% across five vessels (0-1·47%), although skates were usually unhooked manually and did not usually pass through a bait-stripper. AVM in otter trawls averaged 0·76% (0-2·35%), from four vessels fishing with tow durations of <1·5 h (southern North Sea) or 1-4 h (English Channel). No AVM was noted for skates taken as a by-catch in drift trammel nets (soak times <4 h). Anchored tangle nets resulted in an overall AVM of 2·0-2·7%, but increased from 1·47% (13-28 h soak time) to 6·16% (42-53 h soak time). There were significant differences in the vigour of skates between gears, with R. clavata caught by longline and tangle nets in better condition than those captured by otter trawl or drift trammel net. Similarly, R. undulata caught by tangle net were in better condition than those caught by otter trawl. The vigour of R. undulata was also found to be higher than other skate species for both trawl and tangle net. In total, 5283 skates were tagged with Petersen discs and released, with recapture rates for the various combinations of vessel and gear ranging up to 24·8% for R. clavata. Whilst confirming a degree of post-release survival, quantitative estimates of post-release mortality for skates remain unknown.

The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression.

The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.

Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.

Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.

DNA copy number alterations in central primitive neuroectodermal tumors and tumors of the pineal region: an international individual patient data meta-analysis.

Little is known about frequency, association with clinical characteristics, and prognostic impact of DNA copy number alterations (CNA) on survival in central primitive neuroectodermal tumors (CNS-PNET) and tumors of the pineal region. Searches of MEDLINE, Pubmed, and EMBASE--after the original description of comparative genomic hybridization in 1992 and July 2010--identified 15 case series of patients with CNS-PNET and tumors of the pineal region whose tumors were investigated for genome-wide CNA. One additional case study was identified from contact with experts. Individual patient data were extracted from publications or obtained from investigators, and CNAs were converted to a digitized format suitable for data mining and subgroup identification. Summary profiles for genomic imbalances were generated from case-specific data. Overall survival (OS) was estimated using the Kaplan-Meier method, and by univariable and multivariable Cox regression models. In their overall CNA profiles, low grade tumors of the pineal region clearly diverged from CNS-PNET and pineoblastoma. At a median follow-up of 89 months, 7-year OS rates of CNS-PNET, pineoblastoma, and low grade tumors of the pineal region were 22.9 ± 6, 0 ± 0, and 87.5 ± 12 %, respectively. Multivariable analysis revealed that histology (CNS-PNET), age (≤2.5 years), and possibly recurrent CNAs were associated with unfavorable OS. DNA copy number profiling suggests a close relationship between CNS-PNET and pineoblastoma. Low grade tumors of the pineal region differed from CNS-PNET and pineoblastoma. Due to their high biological and clinical variability, a coordinated prospective validation in future studies is necessary to establish robust risk factors.

Surveying the Challenges to Improve Linear Accelerator-based Radiation Therapy in Africa: a Unique Collaborative Platform of All 28 African Countries Offering Such Treatment.

Radiation therapy is a critical component for curative and palliative treatment of cancer and is used in more than half of all patients with cancer. Yet there is a global shortage of access to this treatment, especially in Sub-Saharan Africa, where there is a shortage of technical staff as well as equipment. Linear accelerators (LINACs) offer state-of-the-art treatment, but this technology is expensive to acquire, operate and service, especially for low- and middle-income countries (LMICs), and often their harsh environment negatively affects the performance of LINACs, causing downtime. A global initiative was launched in 2016 to address the technology and system barriers to providing radiation therapy in LMICs through the development of a novel LINAC-based radiation therapy system designed for their challenging environments. As the LINAC prototype design phase progressed, it was recognised that additional information was needed from LMICs on the performance of LINAC components, on variables that may influence machine performance and their association, if any, with equipment downtime. Thus, a survey was developed to collect these data from all countries in Africa that have LINAC-based radiation therapy facilities. In order to understand the extent to which these performance factors are the same or different in high-income countries, facilities in Canada, Switzerland, the UK and the USA were invited to participate in the survey, as was Jordan, a middle-income country. Throughout this process, LMIC representatives have provided input on technology challenges in their respective countries. This report presents the method used to conduct this multilevel study of the macro- and microenvironments, the organisation of departments, the technology, the training and the service models that will provide input into the design of a LINAC prototype for a LINAC-based radiation therapy system that will improve access to radiation therapy and thus improve cancer treatment outcomes. It is important to note that new technology should be introduced in a contextual manner so as not to disrupt existing health systems inadvertently, especially with regards to existing staffing, infrastructure and socioeconomic issues. A detailed analysis of data is underway and will be presented in a follow-up report. Selected preliminary results of the study are the observation that LINAC-based facilities in LMICs experience downtime associated with failures in multileaf collimators and vacuum pumps, as well as power instability. Also, that there is a strong association of gross national product per capita with the number of LINACs per population.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer.

OBJECTIVE: Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy. METHODS: The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 µM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed. RESULTS: The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-µM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p < 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain. CONCLUSIONS: Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining.

New metacentric population of the house mouse (Mus musculus domesticus) found in Valchiavenna, Northern Italy.

Although the standard karyotype of the western house mouse (Mus musculus domesticus) consists entirely of telocentric chromosomes, there are over 100 populations across western Europe and North Africa characterized by different sets of metacentrics formed by Robertsonian fusions and whole-arm reciprocal translocations. Here we report the discovery of a new metacentric population from Valchiavenna, northern Italy, that we have named the 'Lower Valchiavenna population' (abbreviated as ILVC). This metacentric population is found in villages and on farms over a 10-kilometer stretch comprising the southern half of Valchiavenna. ILVC is characterized by the metacentrics 1.18, 2.4, 3.8, 5.15, 6.7, 9.14, 10.12, 11.13 and 16.17, and appears to be closely related to the Chiasso population (CHCH), which possesses the same set of metacentrics except 1.18. We discuss the evolutionary origin of ILVC in relation to human occupation of the region. We also suggest that the geographical position of ILVC between 2 other metacentric populations with entirely different sets of metacentrics (Chiavenna, ICHI, and lower Valtellina, ILVA) may provide 2 additional chromosomal hybrid zones for the study of speciation.

Amplifying small amounts of tumor DNA allows detection of DNA copy number abberations with array-CGH.

Array comparative genomic hybridization (aCGH) is a powerful tool to detect relative DNA copy number at a resolution limited only by the coverage of bacterial artificial chromosomes (BACs) used to print the genomic array. The amount of DNA needed to perform a reliable aCGH analysis has been a limiting factor, especially on minute tissue samples where limited DNA is available. Here we report a simple, highly sensitive and reliable aCGH method to analyze samples of no more than 1 ng genomic DNA. The speed and simplicity of the technique are ideal for studies on small clinical samples such as needle biopsies.

Longevity of anterior resin-bonded bridges: survival rates of two tooth preparation designs.

BACKGROUND: Significant developments have occurred in the design of resin-bonded bridges (RBB) over the past two decades. They are commonly used as an alternative treatment option for a single missing tooth. The longevity of these bridges needs to be further investigated to evaluate long-term outcomes for this option to remain relevant. METHODS: A cohort of patients who received anterior resin-bonded bridges (ARBB) over two decades was studied retrospectively. Longevity of 206 ARBB was assessed using Kaplan-Meier probability estimates. The two modified tooth preparation designs investigated were: (A) mesial and distal vertical grooves only; and (B) one proximal groove adjacent to the pontic and two palatal grooves. Age and gender of the patient cohort were also recorded. RESULTS: Overall survival rate of ARBB was 98% at 5 years, 97.2% at 10 years, and 95.1% from 12 years till 21 years. Survival curves showed minor differences when compared for the two designs, age groups and gender of ARBB recipients. Differences in the proportion of surviving bridges for design A (95.96%) and design B (98.13%) were not statistically significant (Fisher's exact test). CONCLUSIONS: Anterior RBB with described tooth preparation designs demonstrate a high survival rate.

Contribution of Notch signaling activation to human glioblastoma multiforme.

OBJECT: Because activation of Notch receptors has been suggested to be critical for Ras-mediated transformation, and because many gliomas exhibit deregulated Ras signaling, the authors measured Notch levels and activation in primary samples and cell lines derived from glioblastoma multiforme (GBM) as well as the contribution of Notch pathway activation to astrocytic transformation and growth. METHODS: Western blot analysis of Notch 1 expression and activation showed that Notch 1 protein was overexpressed and/or activated in Ras-transformed astrocytes, in three of four GBM cell lines, and in four of five primary GBM samples. Expansion of these studies to assess mRNA expression of components of the Notch signaling pathway by cDNA expression array showed that cDNAs encoding components of the Notch signaling pathway, including the Notch ligand Jagged-1, Notch 3, and the downstream targets of Notch (HES1 and HES2), were also overexpressed relative to non-neoplastic brain controls in 23, 71, and 51% of 35 primary GBMs, respectively. Furthermore, inhibition of Notch signaling by genetic or pharmacological means led to selective suppression of the growth and expression of markers of differentiation in cells exhibiting Notch pathway deregulation. CONCLUSIONS: Notch activation contributes to Ras-induced transformation of glial cells and to glioma growth, survival, or both and as such may represent a new target for GBM therapy.

Hepatic metallothionein and total oxyradical scavenging capacity in Atlantic cod Gadus morhua caged in open sea contamination gradients.

Biological effects monitoring has seldom been undertaken in offshore pelagic environments. Cages containing hatchery-reared Atlantic cod Gadus morhua were deployed on expected contamination gradients, along a transect from the River Elbe in the German Bight, and in the vicinity of an oil field in the North Sea (Statfjord). Six weeks later, the cod were retrieved and samples taken for a range of biological effects techniques. In this study, metallothionein (MT) and total oxyradical scavenging capacity (TOSC) were measured in liver samples from the caged cod, together with metals (as a measure of bioaccumulation). Both MT and TOSC were highest in cod from the German Bight. In the Statfjord samples MT and TOSC decreased with distance from the oil platform indicating induction in response to anthropogenic sources. The bioavailability of metals appears to be a major factor in MT synthesis, and the measurement of MT and associated metals is shown to be a useful tool for biological exposure and effects monitoring in pelagic systems. There also appears to be a strong linkage between MT and TOSC levels, indicating overlapping capabilities as stress biomarkers. Results suggest that in addition to its role as a specific indicator of metal exposure, MT in cod could act as a more general biomarker of oxidative stress under certain conditions.

Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma.

Glioblastoma, the most aggressive primary brain tumor in humans, exhibits a large degree of molecular heterogeneity. Understanding the molecular pathology of a tumor and its linkage to behavior is an important foundation for developing and evaluating approaches to clinical management. Here we integrate array-comparative genomic hybridization and array-based gene expression profiles to identify relationships between DNA copy number aberrations, gene expression alterations, and survival in 34 patients with glioblastoma. Unsupervised clustering on either profile resulted in similar groups of patients, and groups defined by either method were associated with survival. The high concordance between these separate molecular classifications suggested a strong association between alterations on the DNA and RNA levels. We therefore investigated relationships between DNA copy number and gene expression changes. Loss of chromosome 10, a predominant genetic change, was associated not only with changes in the expression of genes located on chromosome 10 but also with genome-wide differences in gene expression. We found that CHI3L1/YKL-40 was significantly associated with both chromosome 10 copy number loss and poorer survival. Immortalized human astrocytes stably transfected with CHI3L1/YKL-40 exhibited changes in gene expression similar to patterns observed in human tumors and conferred radioresistance and increased invasion in vitro. Taken together, the results indicate that integrating DNA and mRNA-based tumor profiles offers the potential for a clinically relevant classification more robust than either method alone and provides a basis for identifying genes important in glioma pathogenesis.

Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients.

BACKGROUND: Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. METHODS: DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. RESULTS: The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. CONCLUSIONS: Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.