Proof-of-Principle Experiment for FEL-Based Coherent Electron Cooling,”

Abstract Coherent electron cooling (CEC) has a potential to significantly boost luminosity of high-energy, highintensity hadron-hadron and electron-hadron colliders. In a CEC system, a hadron beam interacts with a cooling electron beam. A perturbation of the electron density caused by ions is amplified and fed back to the ions to reduce the energy spread and the emittance of the ion beam. To demonstrate the feasibility of CEC we propose a proof-of-principle experiment at RHIC using SRF linac. In this paper, we describe the setup for CeC installed into one of RHIC's interaction regions. We present results of analytical estimates and results of initial simulations of cooling a gold-ion beam at 40 GeV/u energy via CeC

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Ground improvement for enhancing the performance of road, rail, and port infrastructure

A great deal of the world\u27s transport infrastructure is built along congested coastal belts that consist of highly compressible and weak soils with very low bearing capacity and excessive settlement charac-teristics, so stabilising them before construction will guarantee long term and short term stability. Pre-construction consolidation of soft soils via a surcharge load alone often takes too long, and the load required to achieve more than 90% consolidation can be excessively high over a prolonged period, which is why a system of vertical drains combined with vacuum pressure and surcharge preloading has become an attractive alterna-tive for ground improvement. This technique accelerates consolidation by enabling a rapid radial flow which decreases the excess pore pressure while increasing the effective stress. Ballasted railroads form one of the major worldwide transportation networks and they continue to provide quick and safe transportation. As the axle loads and number of high-speed trains\u27 increases, so the quality of track substructure becomes extremely important, and the excessive deformation and degradation of the granular media and unacceptable differential settlement of soft subgrade necessitates frequent track maintenance. To rectify these problems, the use of arti-ficial inclusions in the rail environment has been effective. Field measurements, analytical approach and nu-merical modelling are among the methodologies used to evaluate the effectiveness of these artificial inclu-sions. Comprehensive field trials were carried out to assess the role of geogrids, geocomposite, and shock mats in stabilising ballast embankments at Bulli and Singleton, New South Wales, Australia. Large-scale triaxial tests were conducted to investigate the behaviour of reinforced and un-reinforced subballast under cyclic load using process simulation triaxial apparatus. Geocells influenced the behaviour of subballast under cyclic load-ing, particularly at low confining pressure and high frequency. Coal wash (CW) and basic oxygen steel slag fines (BOS) were used as fill for the reclamation project at the Outer Harbor extension of Port Kembla, at Wollongong, NSW. The laboratory investigation on the optimum CW-BOS mixtures is depicted here. Fur-thermore, a new methodology using a field evaluation of the shear wave velocity (Vs) combined with matric suction (ua-uw) or moisture content was applied to assess compaction at Penrith Lakes, NSW. This paper de-scribes an evaluation of the performance of artificial inclusions and compaction control using laboratory test-ing, analytical approaches, numerical modelling and field measurements

Whey proteins as functional food ingredients?

Graeme H. McIntosh, Peter J. Royle, Richard K. Le Leu, Geoffrey O. Regester, Melissa A. Johnson, Ross L. Grinsted, Rachel S. Kenward, Geoffrey W. Smither

Helical tomotherapy-based STAT RT: Dosimetric evaluation for clinical implementation of a rapid radiation palliation program.

Helical tomotherapy-based STAT radiation therapy (RT) uses an efficient software algorithm for rapid intensity-modulated treatment planning, enabling conformal radiation treatment plans to be generated on megavoltage computed tomography (MVCT) scans for CT simulation, treatment planning, and treatment delivery in one session. We compared helical tomotherapy-based STAT RT dosimetry with standard linac-based 3D conformal plans and standard helical tomotherapy-based intensity-modulated radiation therapy (IMRT) dosimetry for palliative treatments of whole brain, a central obstructive lung mass, multilevel spine disease, and a hip metastasis. Specifically, we compared the conformality, homogeneity, and dose with regional organs at risk (OARs) for each plan as an initial step in the clinical implementation of a STAT RT rapid radiation palliation program. Hypothetical planning target volumes (PTVs) were contoured on an anthropomorphic phantom in the lung, spine, brain, and hip. Treatment plans were created using three planning techniques: 3D conformal on Pinnacle³, helical tomotherapy, and helical tomotherapy-based STAT RT. Plan homogeneity, conformality, and dose to OARs were analyzed and compared. STAT RT and tomotherapy improved conformality indices for spine and lung plans (CI spine = 1.21, 1.17; CI lung = 1.20, 1.07, respectively) in comparison with standard palliative anteroposterior/posteroanterior (AP/PA) treatment plans (CI spine = 7.01, CI lung = 7.30), with better sparing of heart, esophagus, and spinal cord. For palliative whole-brain radiotherapy, STAT RT and tomotherapy reduced maximum and mean doses to the orbits and lens (maximum/mean lens dose: STAT RT = 2.94/2.65 Gy, tomotherapy = 3.13/2.80 Gy, Lateral opposed fields = 7.02/3.65 Gy), with an increased dose to the scalp (mean scalp dose: STAT RT = 16.19 Gy, tomotherapy = 15.61 Gy, lateral opposed fields = 14.01 Gy). For bony metastatic hip lesions, conformality with both tomotherapy techniques (CI = 1.01 each) is superior to AP/PA treatments (CI = 1.21), as expected. Helical tomotherapy-based STAT RT treatment planning provides clinically acceptable dosimetry, with conformality and homogeneity that is superior to standard linac-based 3D conformal planning and is only slightly inferior to standard helical tomotherapy IMRT dosimetry. STAT RT facilitates rapid treatment planning and delivery for palliative radiation of patients with metastatic disease, with relative sparing of adjacent OARs compared with standard 3D conformal plans