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.

Transition between Instability and Seeded Self-Modulation of a Relativistic Particle Bunch in Plasma.

We use a relativistic ionization front to provide various initial transverse wakefield amplitudes for the self-modulation of a long proton bunch in plasma. We show experimentally that, with sufficient initial amplitude [≥(4.1±0.4) MV/m], the phase of the modulation along the bunch is reproducible from event to event, with 3%-7% (of 2π) rms variations all along the bunch. The phase is not reproducible for lower initial amplitudes. We observe the transition between these two regimes. Phase reproducibility is essential for deterministic external injection of particles to be accelerated.

Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: A systematic review and meta-analysis.

BACKGROUND: The aim of the present study was to analyse the incidence, risk ratio (RR) and prognoses of two types of medication-related osteonecrosis of the jaws (MRONJ): denosumab-related osteonecrosis of the jaws (DRONJ) and Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) in cancer patients under treatment with denosumab or zoledronic acid (ZA). MATERIAL AND METHODS: An electronic and manual search was conducted for randomized controlled trials (RCTs) until May 2019. Assessment of the identified studies, risk of bias and data extraction were performed independently by two reviewers. The incidence of DRONJ and BRONJ and the RR to develop MRONJ were calculated at 1 year, 2 years and 3 years of exposure. It was also calculated the odds ratio (OR) of their respective prognoses. They were calculated normalizing the values of the individual studies to 1 year, 2 years or 3 years when necessary through robust regression models using a statistical program. RESULTS: From 1.277 references identified, 8 RCTs were included, which comprised a total of 13.857 patients with a variety of neoplasms. The incidence of DRONJ in cancer patients under treatment with denosumab ranged from 0.5 to 2.1% after 1 year, 1.1 to 3.0% after 2 years, and 1.3 to 3.2% after 3 years of exposure. The incidence of BRONJ in cancer patients under treatment with ZA ranged from 0.4 to 1.6% after 1 year of exposure, 0.8 to 2.1% after 2 years, and 1.0 to 2.3% after 3 years of exposure. Statistically significant differences were found between denosumab and ZA in the risk of developing MRONJ after 1, 2 and 3 years of exposure. Nevertheless, there were no significant differences in terms of patient prognosis. CONCLUSIONS: Denosumab is associated with a significantly higher risk of developing MRONJ compared to ZA. Nevertheless, no differences were found in its prognoses.

Proton Bunch Self-Modulation in Plasma with Density Gradient.

We study experimentally the effect of linear plasma density gradients on the self-modulation of a 400 GeV proton bunch. Results show that a positive or negative gradient increases or decreases the number of microbunches and the relative charge per microbunch observed after 10 m of plasma. The measured modulation frequency also increases or decreases. With the largest positive gradient we observe two frequencies in the modulation power spectrum. Results are consistent with changes in wakefields' phase velocity due to plasma density gradients adding to the slow wakefields' phase velocity during self-modulation growth predicted by linear theory.

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'.

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.

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.

New horizons in anticoagulation: Direct oral anticoagulants and their implications in oral surgery.

BACKGROUND: Thrombotic disorders remain a leading cause of death in the Western World. For decades, vitamin K antagonists used in the prevention of this pathology, such as warfarin or sintrom, were the only oral agents available for long-term anticoagulation, in spite of their disadvantages. MATERIAL AND METHODS: An electronic database search was carried out on MedLine and The Cochrane Library Plus, without restrictions on the type of study nor dates, in English and Spanish. Abstracts were reviewed, and complete articles if necessary, considering all articles that included recommendations on DOACs and oral surgery. RESULTS: In recent years, the so-called "new oral anticoagulants" have been introduced in clinical practice to treat those patients whose medical conditions require long-term anticoagulant treatment, replacing traditional oral anticoagulants. CONCLUSIONS: The new oral anticoagulants represent new therapeutic options, with a number of advantages such as poor interaction with food, minor drug interactions, and do not require periodic dose adjustments or routine controls. The purpose of this review is to establish an update on the new oral anticoagulants: Dabigatran, Rivarozaban, Apixaban and Edoxaban.

Surgical complications in zygomatic implants: A systematic review.

BACKGROUND: The use of zygomatic implants in the prosthetic rehabilitation of the patient with severe maxillary bone atrophy is another therapeutic alternative, not exempt from complications. The main objective of this review is to analyze and describe the most frequent surgical complications associated with the use of zygomatic implants. MATERIAL AND METHODS: An electronic database search on PubMed, along with a manual search, without taking into account date nor language, was undertaken by two observers, selecting studies that comprised a study period from 6 to 12 months, any type of clinical trial, and series that included a follow-up and/or review period during the aforementioned margin, that mentioned at least two types of complications. RESULTS: Out of the initial search that yielded 455 studies, 67 were considered potentially relevant for the present study, out of which 14 were finally selected. Out of the most frequent surgical complications, sinusitis (3,9%) and failure in osseointegration (2,44%) are highlighted. CONCLUSIONS: The analysis of the results shows that the most frequent complications are sinusitis and failure in osseointegration of the zygomatic implant. However, a standardised data collection system for the data on complications is needed.

Elimination of extracellular dopamine in the medial prefrontal cortex of conscious mice analysed using selective enzyme and uptake inhibitors.

We have shown in a previous study that in the medial prefrontal cortex (mPFC) of Comt knockout animals, uptake1 followed by oxidation accounts for approximately 50% and uptake2 followed by O-methylation for the remaining 50% of dopamine clearance. However, compensatory mechanisms in genetically modified animals may have affected the result. Therefore, in the present study, we gave a high dose (30 mg/kg) of tolcapone in combination with pargyline and reboxetine to C57BL/6J mice to see whether the earlier findings could be confirmed. The three drugs were also given together. We used intracerebral microdialysis to determine the levels of extracellular dopamine and its metabolites in the mPFC. In addition, we analyzed dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) contents in cortical and striatal synaptosomes to estimate the amount of releasable dopamine and dopamine turnover. In the prefrontal cortex of male C57BL/6J mice, the combination of two drugs (pargyline + tolcapone or reboxetine + tolcapone) generally elevated extracellular dopamine levels more than any single drug. Similar responses, although much weaker, were observed in female mice. Unexpectedly, triple treatment with pargyline, reboxetine and tolcapone did not increase dopamine outflow in the mPFC in either sex, and the treatment actually diminished dopamine outflow in the dorsal striatum. This seems to indicate that such an extensive treatment induces a fast and effective shut-down of dopamine release both in the mPFC and striatum to protect the brain from excess dopaminergic stimulation. The observed decrease in extracellular dopamine levels was not due to the depletion of releasable dopamine because abundant amounts of dopamine were present in synaptosomes. These results imply that the relative proportion of COMT-induced dopamine clearance may be somewhat lower than earlier estimated.

Generation of membrane-bound catechol-O-methyl transferase deficient mice with disctinct sex dependent behavioral phenotype.

Catechol-O-methyltransferase (COMT) has two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-MT), anchored to intracellular membranes. COMT is involved in the O-methylation of L-DOPA, dopamine and other catechols. The exact role of MB-COMT is still mostly unclear. We wanted to create a novel genetically modified mouse model that specifically lacks MB-COMT activity and to study their behavioral phenotype. MB-COMT knock-in mutant mice were generated by introducing two point mutations in exon 2 of the Comt gene (ATGCTG->GAGCTC disabling the function of the P2 promoter and allowing only the P1-regulated S-COMT transcription. The first mutation changes methionine to glutamic acid whereas the second one does not affect coding. The expression of the two COMT isoforms, total COMT activity in several areas of the brain and peripheral tissues and extracellular dopamine concentrations after L-DOPA (10 mg/kg) and carbidopa (30 mg/kg) subcutaneous administration were assessed. A battery of behavioral tests was performed to compare MB-COMT deficient mice and their wild type littermates of both sexes. MB-COMT deficient mice were seemingly normal, bred usually and had unaltered COMT activity in the brain and periphery despite a complete lack of the MB-COMT protein. MB-COMT deficient male mice showed higher extracellular dopamine levels than their wild-type littermates in the striatum, but not in the mPFC. In addition, the MB-COMT deficient male mice exhibited a distinct endophenotype characterized by schizophrenia-related behaviors like aggressive behavior and reduced prepulse inhibition. They also had prolonged immobility in the tail suspension test. Both sexes were sensitized to acute pain and had normal motor activity but disturbed short-term memory. Hence the behavioral phenotype was not limited to schizophrenia-related endophenotype and some behavioural findings were not sex-dependent. Our findings indicate that MB-COMT is critical for behavior, and its function in COMT-dependent brain areas cannot be entirely substituted by the remaining S-COMT.

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.

Minimum 6year results of an uncemented trabecular metal tibial component in total knee arthroplasty.

INTRODUCTION: There are theoretical advantages of using a trabecular metal tibial component in total knee replacement (TKR) for long-term survival. We have previously reported outcomes at 3 years. We now report the clinical and radiological outcome of an unselected series of 109 knees at a minimum of 6 years follow up. METHODS: Patient function was assessed in a research clinic using Oxford Knee Score (OKS), Clinical and Functional Knee Society Score (KSS) and SF-12 physical score. Up to date weight bearing radiographs were obtained. RESULTS: Seventy-six knees in 72 patients were available for assessment. OKS scores were maintained from the 3-year assessment with a mean of 36.1 (8.6). KSS and SF-12 scores declined slightly but only to a degree previously reported as normal age related change. The mean KSS at follow up was 87.2 (17.7). There was no radiographic evidence of loosening in any implant. There has been 1 revision for unexplained pain at 27 months. CONCLUSION: The uncemented TMT in an unselected group is performing as well as any TKR implant at this stage. Future follow up is required to ensure this is maintained. The theoretical advantages may make this the prosthesis of choice in younger patients. LEVEL OF EVIDENCE: IV. Case series.

Opportunities for public water utilities in the market of energy from water.

An inventory is made of the possibilities to recover sustainable energy from the water cycle by identifying different water flows in a municipal environment as a sustainable energy source. It is discussed what role public water utilities should play in the market of energy from water. This is done for Waternet, the public water utility of Amsterdam, by describing experiences on two practical applications for aquifer thermal energy storage and energy recovery from drinking water. The main conclusion is that public water utilities can substantially contribute to the production of sustainable energy, especially by making use of heat and cold from the water cycle. Public water utilities have the opportunity to both regulate and enter the market for energy from water.

Behavioral profile of mice with impaired cognition in the elevated plus-maze due to a deficiency in neural cell adhesion molecule.

The elevated plus-maze (EPM) test is one of the most used tests for screening levels of anxiety in rodents. In the present study, we studied how impaired cognition due to a deficiency in the neural cell adhesion molecule (NCAM) could affect the behavior of mice in the EPM task. NCAM-knockout mice demonstrated impaired learning in both object-recognition and fear-conditioning tasks. Analysis of the behavior of mice in the EPM task using a minute-by-minute method revealed a profound influence of genotype. Wild-type mice demonstrated quick learning of the aversive properties of the open arms during the first few minutes of a single EPM task, whereas NCAM-/- mice were unable to learn the aversive properties of the open arms of EPM. Wild-type mice also demonstrated habituation to the EPM task in a test/retest paradigm whereas NCAM-knockout mice failed to habituate during the second EPM presentation. Our data show that the anxiolytic-like behavior of NCAM-knockout mice is not just related to levels of innate anxiety but also to their inability to recognize potential danger associated with the open arms of the EPM task.

Arthroscopic anterior cruciate ligament surgery: results of autogenous patellar tendon graft versus the Leeds-Keio synthetic graft five year follow-up of a prospective randomised controlled trial.

We conducted a prospective, randomised controlled trial comparing anterior cruciate ligament reconstruction using middle third patellar tendon graft (PT) to synthetic Leeds-Keio (LK) ligament. The patients were randomised (26 PT, 24 LK). Subjective knee function was classified (Lysholm, Tegner activity, IKDC scores), laxity was measured (Lachman test, Stryker laxometer), and functional ability was assessed (one-hop test). There were no significant differences between Lysholm or IKDC scores at any stage by 5 years. Significant differences were found between the groups at 2 years for Tegner activity scores, laxity and one-hop testing. By 5 years there were no significant differences. Clinical equivalence was demonstrated between the two groups for the Lysholm score and one-hop test but not for the Tegner activity score at 5 years. The use of the LK ligament has been largely abandoned due to reports of its insufficiency. Our results demonstrate that it is not as inferior as one might expect. We conclude that the results of LK ligament ACL reconstruction are as acceptable as those using PT. It may provide an additional means of reconstruction where no suitable alternative is present.

Use of on-line UV/Vis-spectrometry in the measurement of dissolved ozone and AOC concentrations in drinking water treatment.

The concentrations of dissolved ozone and assimilable organic carbon (AOC) are important performance parameters in drinking water production. For the measurement of ozone, a spectral algorithm was developed that allows quantification in situ using a UV/Vis spectrometer probe. Furthermore, a strong correlation between the change in the absorption spectrum after individual treatment steps and the formation or removal of AOC in that treatment step was observed. This allowed the development of a spectral algorithm that predicts AOC formation during ozonation and subsequent removal in further treatment steps. This method has been verified at one pilot plant of the Amsterdam drinking water supply.

Migratory response of European eel (Anguilla anguilla) phagocytes to the eel swimbladder nematode Anguillicola crassus.

The migratory response of peripheral blood granulocytes and monocytes from the European eel Anguilla anguilla (L.) to infective larvae of the swimbladder nematode Anguillicola crassus Kuwahara, Niimi and Hagaki, 1974 was examined by means of light microscopical histology and with an in vitro assay using a modified Boyden chamber. Histological examination of experimentally infected eels revealed that, already 8 days postinfection, an infiltration of inflammatory cells around L3 of A. crassus in the swimbladder tissue can occur. In the Boyden chamber, in presence of infective larvae of A. crassus (L3), neutrophil granulocytes and monocytes showed a higher migration activity than in the absence of L3. In conclusion, infection of European eels with A. crassus leads to an activation of the defence cells resulting in an increased migration activity compared to uninfected eels.