Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Industrial scale bio-detoxification of raw olive mill wastewaters by the use of selected microbial yeast and bacterial strains to obtain a new source for fertigation.

The Olive Mill Wastewaters (OMWs) are one of the most important agro-industrial wastes of the Mediterranean Countries and the disposal by draining them onto land has been proved to be damaging for soils, plants and groundwater due to their polluting power. The present report describes a new method for bio-detoxification of undiluted fresh OMW based on the driven selection of aerobic yeasts and bacteria. The identified yeast Candida boidinii A5y and the bacterium Paenibacillus albidus R32b strains allowed the treatment of freshly produced raw OMW characterized by very high COD value and phenolic content, when applied as sequential inoculum. The treated OMW showed the absence of antimicrobial effects and a strongly reduction of phytotoxic activity on the germination of several plant seeds. The process was successfully validated on an industrial scale without any pre-treatment, dilution and/or supplementation of the raw waste. Bio-detoxified OMW produced by this sustainable and low-cost process would be suitable for new non-chemical fertigation or soilless applications. The described procedure represents a virtuous example of circular economy efficaciously applied for a depleting agri-food resource.

Multidisciplinary European Low Dose Initiative (MELODI): strategic research agenda for low dose radiation risk research.

MELODI (Multidisciplinary European Low Dose Initiative) is a European radiation protection research platform with focus on research on health risks after exposure to low-dose ionising radiation. It was founded in 2010 and currently includes 44 members from 18 countries. A major activity of MELODI is the continuous development of a long-term European Strategic Research Agenda (SRA) on low-dose risk for radiation protection. The SRA is intended to identify priorities for national and European radiation protection research programs as a basis for the preparation of competitive calls at the European level. Among those key priorities is the improvement of health risk estimates for exposures close to the dose limits for workers and to reference levels for the population in emergency situations. Another activity of MELODI is to ensure the availability of European key infrastructures for research activities, and the long-term maintenance of competences in radiation research via an integrated European approach for training and education. The MELODI SRA identifies three key research topics in low dose or low dose-rate radiation risk research: (1) dose and dose rate dependence of cancer risk, (2) radiation-induced non-cancer effects and (3) individual radiation sensitivity. The research required to improve the evidence base for each of the three key topics relates to three research lines: (1) research to improve understanding of the mechanisms contributing to radiogenic diseases, (2) epidemiological research to improve health risk evaluation of radiation exposure and (3) research to address the effects and risks associated with internal exposures, differing radiation qualities and inhomogeneous exposures. The full SRA and associated documents can be downloaded from the MELODI website ( http://www.melodi-online.eu/sra.html ).

How old are you? Genet age estimates in a clonal animal.

Foundation species such as redwoods, seagrasses and corals are often long-lived and clonal. Genets may consist of hundreds of members (ramets) and originated hundreds to thousands of years ago. As climate change and other stressors exert selection pressure on species, the demography of populations changes. Yet, because size does not indicate age in clonal organisms, demographic models are missing data necessary to predict the resilience of many foundation species. Here, we correlate somatic mutations with genet age of corals and provide the first, preliminary estimates of genet age in a colonial animal. We observed somatic mutations at five microsatellite loci in rangewide samples of the endangered coral, Acropora palmata (n = 3352). Colonies harboured 342 unique mutations in 147 genets. Genet age ranged from 30 to 838 years assuming a mutation rate of 1.195-04 per locus per year based on colony growth rates and 236 to 6500 years assuming a mutation rate of 1.542-05 per locus per year based on sea level changes to habitat availability. Long-lived A. palmata genets imply a large capacity to tolerate past environmental change, and yet recent mass mortality events in A. palmata suggest that capacity is now being frequently exceeded.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

A lysigenic programmed cell death-dependent process shapes schizogenously formed aerenchyma in the stems of the waterweed Egeria densa.

BACKGROUND AND AIMS: Plant adaptation to submergence can include the formation of prominent aerenchyma to facilitate gas exchange. The aim of this study was to characterize the differentiation of the constitutive aerenchyma in the stem of the aquatic macrophyte Egeria densa (Hydrocharitaceae) and to verify if any form of cell death might be involved. METHODS: Plants were collected from a pool in a botanical garden. Aerenchyma differentiation and apoptotic hallmarks were investigated by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay coupled with genomic DNA extraction and gel electrophoresis (DNA laddering assay). Cell viability and the occurrence of peroxides and nitric oxide (NO) were determined histochemically using specific fluorogenic probes. KEY RESULTS: Aerenchyma differentiation started from a hexagonally packed pre-aerenchymatic tissue and, following a basipetal and centripetal developmental pattern, produced a honeycomb arrangement. After an early schizogenous differentiation process, a late lysigenous programmed cell death- (PCD) dependent mechanism occurred. This was characterized by a number of typical apoptotic hallmarks, including DNA fragmentation, chromatin condensation, apoptotic-like bodies, partial cell wall lysis and plasmolysis. In addition, local increases in H2O2 and NO were observed and quantified. CONCLUSIONS: The differentiation of cortical aerenchyma in the stem of E. densa is a complex process, consisting of a combination of an early schizogenous differentiation mechanism and a late lysigenous PCD-dependent process. The PCD remodels the architecture of the gas spaces previously formed schizogenously, and also results in a reduction of O2-consuming cells and in recycling of material derived from the lysigenic dismantling of the cells.

Fate of D3 mouse embryonic stem cells exposed to X-rays or carbon ions.

The risk of radiation exposure during embryonic development is still a major problem in radiotoxicology. In this study we investigated the response of the murine embryonic stem cell (mESC) line D3 to two radiation qualities: sparsely ionizing X-rays and densely ionizing carbon ions. We analyzed clonogenic cell survival, proliferation, induction of chromosome aberrations as well as the capability of cells to differentiate to beating cardiomyocytes up to 3 days after exposure. Our results show that, for all endpoints investigated, carbon ions are more effective than X-rays at the same radiation dose. Additionally, in long term studies (≥8 days post-irradiation) chromosomal damage and the pluripotency state were investigated. These studies reveal that pluripotency markers are present in the progeny of cells surviving the exposure to both radiation types. However, only in the progeny of X-ray exposed cells the aberration frequency was comparable to that of the control population, while the progeny of carbon ion irradiated cells harbored significantly more aberrations than the control, generally translocations. We conclude that cells surviving the radiation exposure maintain pluripotency but may carry stable chromosomal rearrangements after densely ionizing radiation.

Deep learning-based voxel sampling for particle therapy treatment planning.

Objective.Scanned particle therapy often requires complex treatment plans, robust optimization, as well as treatment adaptation. Plan optimization is especially complicated for heavy ions due to the variable relative biological effectiveness. We present a novel deep-learning model to select a subset of voxels in the planning process thus reducing the planning problem size for improved computational efficiency.Approach.Using only a subset of the voxels in target and organs at risk (OARs) we produced high-quality treatment plans, but heuristic selection strategies require manual input. We designed a deep-learning model based onP-Net to obtain an optimal voxel sampling without relying on patient-specific user input. A cohort of 70 head and neck patients that received carbon ion therapy was used for model training (50), validation (10) and testing (10). For training, a total of 12 500 carbon ion plans were optimized, using a highly efficient artificial intelligence (AI) infrastructure implemented into a research treatment planning platform. A custom loss function increased sampling density in underdosed regions, while aiming to reduce the total number of voxels.Main results.On the test dataset, the number of voxels in the optimization could be reduced by 84.8% (median) at <1% median loss in plan quality. When the model was trained to reduce sampling in the target only while keeping all voxels in OARs, a median reduction up to 71.6% was achieved, with 0.5% loss in the plan quality. The optimization time was reduced by a factor of 7.5 for the total AI selection model and a factor of 3.7 for the model with only target selection.Significance.The novel deep-learning voxel sampling technique achieves a significant reduction in computational time with a negligible loss in the plan quality. The reduction in optimization time can be especially useful for future real-time adaptation strategies.

From DNA damage to chromosome aberrations: joining the break.

Despite many years of experimental studies on radiation-induced chromosomal aberrations, and the recent progress in elucidating the molecular mechanisms of the DNA damage response, the link between DNA double-strand break repair and its expression as microscopically visible chromosomal rearrangements remains, in many ways, obscure. Some long standing controversies have partially been resolved to the satisfaction of most investigators, including the linearity of the dose-response for DNA double-strand break induction, the necessity of pairwise interaction of radiogenic damaged sites in the formation of exchange aberrations, and the importance of proximity between lesions in misrejoining. However, the contribution of different molecular DNA repair mechanisms (e.g., alternative end-joining pathways) and their impact on the kinetics of aberration formation is still unclear, as is the definition of "complex" radiogenic damaged sites - in either the chemical or spatial sense - which ostensibly lead to chromosome rearrangements. These topics have been recently debated by molecular biologists and cytogeneticists, whose opinions are summarized in this paper.

Are charged particles a good match for combination with immunotherapy? Current knowledge and perspectives.

Charged particle radiotherapy, mainly using protons and carbon ions, provides physical characteristics allowing for a volume conformal irradiation and a reduction of the integral dose to normal tissue. Carbon ion therapy additionally features an increased biological effectiveness resulting in peculiar molecular effects. Immunotherapy, mostly performed with immune checkpoint inhibitors, is nowadays considered a pillar in cancer therapy. Based on the advantageous features of charged particle radiotherapy, we review pre-clinical evidence revealing a strong potential of its combination with immunotherapy. We argue that the combination therapy deserves further investigation with the aim of translation in clinics, where a few studies have been set up already.

Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar.

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing.

Quasi-real-time range monitoring by in-beam PET: a case for 15O.

A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of [Formula: see text]O and [Formula: see text]O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters [Formula: see text]C and [Formula: see text]C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for [Formula: see text]C compared to [Formula: see text]C and likewise for [Formula: see text]O compared to [Formula: see text]O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than [Formula: see text]C, [Formula: see text]O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to [Formula: see text]C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, [Formula: see text]O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread.

Live cell microscopy analysis of radiation-induced DNA double-strand break motion.

We studied the spatiotemporal organization of DNA damage processing by live cell microscopy analysis in human cells. In unirradiated U2OS osteosarcoma and HeLa cancer cells, a fast confined and Brownian-like motion of DNA repair protein foci was observed, which was not altered by radiation. By analyzing the motional activity of GFP-53BP1 foci in live cells up to 12-h after irradiation, we detected an additional slower mobility of damaged chromatin sites showing a mean square displacement of approximately 0.6 microm(2)/h after exposure to densely- or sparsely-ionizing radiation, most likely driven by normal diffusion of chromatin. Only occasionally, larger translational motion connected to morphological changes of the whole nucleus could be observed. In addition, there was no general tendency to form repair clusters in the irradiated cells. We conclude that long-range displacements of damaged chromatin domains do not generally occur during DNA double-strand break repair after introduction of multiple damaged sites by charged particles. The occasional and in part transient appearance of cluster formation of radiation-induced foci may represent a higher mobility of chromatin along the ion trajectory. These observations support the hypothesis that spatial proximity of DNA breaks is required for the formation of radiation-induced chromosomal exchanges.

[The network of palliative care for persons with incurable disease in the Local Health Agency n. 7 of the Veneto region]. / La rete di cure palliatiave per malati non guaribili dell'Azien- da Ulss 7 del Veneto.

Only 20% of terminally ill people with cancer in Italy are assisted by a network of palliative care, whereas the majority of them die in the hospital, against their will, and with very low doses of opioids. A palliative care service, is offered by the Nucleus of Palliative care within the Operative Unit of District Primary Care in the local health agency n. 7 of Pieve di Soligo. This service takes charge of the patient from hospital discharge until his/her death, working in concert with the inpatieint hospitals and other territorial health care structures. In this way, the patient and his/her family are followed by a team of professionals working together in coordination and collaboration. In 2010 the percentage of terminally ill persons enrolled in the program was 52%, much greater than the standard of 45% required by ministerial law (DM no 43 del 2007) for the local health agencies without a hospice. The duration of time spent at home during the last phases of the illness was over 90% of time in care, with an in-home mortality of 63%. The consumption of major opioids was amongst the highest in Italy. Thanks to the opening of a hospice, already planned, we will be able to take charge within the network of palliative care thos sick people who cannot remain in the home and extend the service to ill persons without cancer in conditions of advanced incurable disease and end of life.

The genus Aphis (Hemiptera, Aphididae) living on Asteraceae species in southern South America: Argentina and Chile, with five new species.

In the whole of Argentina and Chile, southern South America in this paper, 20 species of the genus Aphis hosted in species of Asteraceae were known; eleven of them are native South American, and those introduced are mostly polyphagous and widespread. The Chilean regions and the Argentine provinces in which each one of them is known, as well as the host plants on which it has been recorded, are listed. New data of 15 of them are presented, with several first records in different Argentine provinces or hosted on diverse plants: The knowledge of A. conspicua and A. fuentesi, which were recently described living on species of Baccharis, is improved from specimens respectively collected on Senecio and Gutierrezia. A. rogerblackmani Nieto Nafra, Ortego Mier Durante sp. n. is described from apterous and alate viviparous females, oviparous females and males collected on Baccharis in Argentina. Other four species are described from apterous and alate viviparae: A. gutierreziae Ortego, Mier Durante Nieto Nafra sp. n., collected on species of Gutierrezia in Argentina, A. hyalis Mier Durante, Nieto Nafra Ortego sp. n., collected on Hyalis argentea in Argentina, A. pulverea Nieto Nafra, Moreno-Gonzlez Ortego sp. n., collected on species of Senecio in Chile and Argentina, and A. sanrafaelina Ortego, Mier Durante Nieto Nafra sp. n., collected on Tagetes mendocina, Thymophylla pentachaeta and Pectis odorata in Argentina. The intraspecific diversity of Aphis pulverea has been analysed by a principal component analysis followed by hierarchical clustering of principal components. An identification key to viviparous females of the species of Aphis hosted in Asteraceae and known in southern South America is presented.

Aphis mirabilis sp. n. (Hemiptera, Aphididae, Aphidina), a South American species resembling A. craccivora, and further data on A. tropaeoli.

We examined 1367 apterous viviparae from 151 samples to study Aphis craccivora, A. tropaeoli and a third, possibly new species in Argentina, resembling both. Principal component analysis (PCA), followed by hierarchical clustering of principal components (HCPC), revealed clusters based on 33 morphological characters of 206 selected specimens. The delimitation of possible taxonomic entities was assessed by logistic regression. PCA confirmed that A. tropaeoli is a valid species. HCPC revealed the existence of a new species distinct from A. craccivora. Recently published data on the variability of A. craccivora, mainly regarding Asian populations, are presented and discussed; the general appearance of the sexuals of this species is also presented. The new species is described with the name Aphis mirabilis Nieto Nafra and Ortego sp. n., based on apterous and alate viviparae, oviparae, and males collected in Mendoza and Neuqun (Argentina) on Adesmia volckmannii (Fabaceae), Atriplex nummularia and At. lampa (Amaranthaceae), Bougainvillea spinosa (Nyctaginaceae), and Robinia pseudoacacia (Fabaceae). This new species has also been collected on plants of another 18 species from 8 additional families, although these specimens are not included in the type series. Features to distinguish A. mirabilis Nieto Nafra and Ortego sp. n. from A. craccivora are presented together with a logistic regression model. The males of A. tropaeoli are described. The list of host plants of A. craccivora in Argentina is updated.

Blanchardaphis poikila syn. n. to B. capitophoroides and Blanchardaphis syn. n. to Lambersius (Hemiptera, Aphididae, Aphidinae, Macrosiphini, Uroleucon).

Blanchardaphis was erected for two Argentinian species of aphids very similar to Uroleucon, but distinguished by several characters. Here, we examined morphology and DNA sequences of Blanchardaphis specimens from Argentina and Chile. We further conducted a phylogenetic analysis to determine the relationship of Blanchardaphis to Uroleucon. We found minor morphological and genetic differences between Blanchardaphis samples based on geography, which appear to be population-level variation. On the basis of current evidence, we conclude that B. poikila (Ortego, Nieto Nafra Mier Durante, 1997) is synonymous with B. capitophoroides (Blanchard, 1942), and that Blanchardaphis Ortego, Nieto Nafra Mier Durante, 1998 is synonymous with Lambersius Olive, 1965 (subgenus of Uroleucon) sensu Nieto Nafra et al. 2007 or alternatively with the subgenus Uroleucon.

Precision of the PET activity range during irradiation with10C,11C, and12C beams.

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable12C ions, the positron emitters10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam.Approach.An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner.Main results.High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes11C and10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for10C,11C and12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from11C to10C than when going from12C to11C. The much better precision for10C is due to its much shorter half-life, which, contrary to the case of11C, also enables to include the in-spill data in the image formation.Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

Interaction of therapeutic12C ions with bone-like targets: physical characterization and dosimetric effect at material interfaces.

Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion.

DNA double strand breaks and chromosomal aberrations.

DNA double strand breaks (DSBs) are ultimate lesions for the formation of chromosomal aberrations (CAs). The formation of CAs is dependent on many factors; some of these are discussed in this review. FISH methodologies have uncovered CA types which cannot be seen with the classical staining methods, and thereby widened our understanding of the origin of CAs. The mobility of DSBs in interphase nuclei is limited. This makes it especially difficult to understand the origin of complex CAs involving many chromosomes. Even using high-resolution mBAND FISH to analyze CAs, the ratio of inter-/intrachromosomal CAs is higher than 1. From this it was postulated that only a subset of DSBs, namely, complex or clustered DSBs give rise mainly to interchromosomal CAs. The finding that endonucleases induce CAs does not fit the idea of complex DSBs being responsible for CA. Probably it is the proximity and not the complexity of DSBs which leads to CA.