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Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs 2 onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Stable and uniform beams with low divergence are required in particle accelerators; therefore, beyond the accelerated current, measuring the beam current spatial uniformity and stability over time is necessary to assess the beam performance, since these parameters affect the perveance and thus the beam optics. For high-power beams operating with long pulses, it is convenient to directly measure these current parameters with a non-intercepting system due to the heat management requirement. Such a system needs to be capable of operating in a vacuum in the presence of strong electromagnetic fields and overvoltages, due to electrical breakdowns in the accelerator. Finally, the measure of the beam current needs to be efficiently integrated into a pulse file with the other relevant plant parameters to allow the data analyses required for beam optimization. This paper describes the development, design and commissioning of such a non-intercepting system, the so-called beamlet current monitor (BCM), aimed to directly measure the electric current of a particle beam. In particular, the layout of the system was adapted to the SPIDER experiment, the ion source (IS) prototype of the heating neutral beam injectors (HNB) for the ITER fusion reactor. The diagnostic is suitable to provide the electric current of five beamlets from DC up to 10 MHz.

Giant negative ion sources for neutral beam injectors deliver huge negative ion currents, thanks to their multi-beamlet configuration. As the single-beamlet optics defines the transmission losses along the beamline, the extraction of a similar current for all beamlets is extremely desirable, in order to facilitate the beam source operation (i.e., around perveance match). This Review investigates the correlation between the vertical profile of beam intensity and the vertical profiles of plasma properties at the extraction region of the source, focusing on the influence of increasing cesium injection. Only by the combined use of all available source diagnostics, described in this Review, can beam features on the scale of the non-uniformities be investigated with a sufficient space resolution. At RF power of 50 kW/driver, with intermediate bias currents and a filter field of 2.4 mT, it is found that the central part of the four vertical beam segments exhibits comparable plasma density and beamlet currents; at the edges of the central segments, both the beam and electron density appear to decrease (probably maintaining fixed electron-to-ion ratio); at the bottom of the source, an increase of cesium injection can compensate for the vertical drifts that cause a much higher presence of electrons and a lower amount of negative ions.

The neutral beam injectors of the ITER experiment will rely on negative ion sources to produce 16.7 MW beams of H/D particles accelerated at 1 MeV. The prototype of these sources was built and is currently operated in the SPIDER (Source for the Production of Ions of Deuterium Extracted from a Radio frequency plasma) experiment, part of the Neutral Beam Test Facility of Consorzio RFX, Padua. In the SPIDER, the H - /D - ion source is coupled to a three grid, 100 kV acceleration system. One of the main goals of the experimentation in SPIDER is to uniformly maximize the extracted current density; to achieve this, it is important to study the density of negative ions available in the proximity of the ion acceleration system. In SPIDER, line-integrated measurements of negative ion density are performed by a cavity ring down spectroscopy diagnostic. Its principle of operation is based on the absorption of the photons of a laser beam pulse by H - /D - photo-detachment; the absorption detection is enhanced by trapping the laser pulse in an optical cavity, containing the absorbing medium (i.e., negative ions). This paper presents and discusses the CRDS diagnostic setup in the SPIDER, including the first measurements of negative ion density, correlated with the main source parameters.

The requirements of ITER neutral beam injectors (1 MeV, 40 A negative deuterium ion current for 1 h) have never been simultaneously attained; therefore, a dedicated Neutral Beam Test Facility (NBTF) was set up at Consorzio RFX (Padova, Italy). The NBTF includes two experiments: SPIDER (Source for the Production of Ions of Deuterium Extracted from Rf plasma), the full-scale prototype of the source of ITER injectors, with a 100 keV accelerator, to investigate and optimize the properties of the ion source; and MITICA, the full-scale prototype of the entire injector, devoted to the issues related to the accelerator, including voltage holding at low gas pressure. The present paper gives an account of the status of the procurements, of the timeline, and of the voltage holding tests and experiments for MITICA. As for SPIDER, the first year of operation is described, regarding the solution of some issues connected with the radiofrequency power, the source operation, and the characterization of the first negative ion beam.

Optical Emission Spectroscopy (OES) on the SPIDER negative ion source has been collecting data since the beginning of operation in Summer 2018. The first few months were devoted to complete the diagnostic commissioning and its integration with the SPIDER control and data acquisition system. Consistent sets of spectroscopic data have been acquired under different experimental conditions, not only varying the plasma source filling pressure and injected power but also changing the RF generator frequencies and the strength of the magnetic field acting as a filter in front of the plasma grid. The main results of OES data analysis are presented in this work. SPIDER optical emission diagnostic comprises a set of 66 channels wavelength resolved and 36 single line channels by means of interference filtering. Some of them collect the photons along line of sight (LOS) perpendicular to the grids through the 8 RF drivers and others along LOS parallel to and near the grids, both horizontally and vertically. Since the starting of extraction experiments, 22 channels have been dedicated to collect the extracted beam emission. The LOS layout allows tracing two 9-point vertical profiles of the source plasma in the extraction region at 35 and 5 mm from the Plasma Grid (PG) and four 4-point horizontal profiles spanning the 65 mm region before the PG. It is also possible to collect spectra from LOS looking in between the grids. Both Balmer series and Fulcher band between 600 nm and 640 nm were routinely collected. Their intensities are very sensitive to the plasma parameters and when coupled to a collisional radiative model can give an estimation of the electron density and gas dissociation. It has been found that the Balmer emission and gas dissociation inside the drivers scale linearly with the RF power, the latter reaching a value up to 20% at high power and low pressure. Rotational gas temperature has also been evaluated; it ranged between 900 K and 1400 K, where higher values were reached for higher pressures and RF powers.

The edge of fusion experiments is a region where strong gradients develop, together with the presence of strong fluctuations due to turbulence. The thermal helium beam diagnostic developed for the RFX-mod experiment allows the measurements with a single diagnostic of both low frequency time evolution of the edge radial profiles of electron density and temperature (tens of hertz), and the high frequency fluctuations (hundreds of kHz). To maximize the collected light, the three HeI lines necessary to be measured for the evaluation of n(e) and T(e) are separated with a spectrograph, and multianode photomultipliers are used as light detectors. The paper describes the diagnostic setup, with the interface hardware with the machine and the optical layout, and the characterization of its performances.

A prototype system of the Langmuir probes for SPIDER (Source for the production of Ions of Deuterium Extracted from RF plasma) was manufactured and experimentally qualified. The diagnostic was operated in RF (Radio Frequency) plasmas with cesium evaporation on the BATMAN (BAvarian Test MAchine for Negative ions) test facility, which can provide plasma conditions as expected in the SPIDER source. A RF passive compensation circuit was realised to operate the Langmuir probes in RF plasmas. The sensors' holder, designed to better simulate the bias plate conditions in SPIDER, was exposed to a severe experimental campaign in BATMAN with cesium evaporation. No detrimental effect on the diagnostic due to cesium evaporation was found during the exposure to the BATMAN plasma and in particular the insulation of the electrodes was preserved. The paper presents the system prototype, the RF compensation circuit, the acquisition system (as foreseen in SPIDER), and the results obtained during the experimental campaigns.

A system of electrostatic sensors has been designed for the SPIDER (Source for the production of Ions of Deuterium Extracted from RF plasma) experiment, prototype RF source of the ITER NBI (neutral beam injection). A prototype of the sensor system was manufactured and tested at the BATMAN (BAvarian Test MAchine for Negative ions) facility, where the plasma environment is similar to that of SPIDER. Different aspects concerning the mechanical manufacturing and the signal conditioning are presented, among them the RF compensation adopted to reduce the RF effects which could lead to overestimated values of the electron temperature. The first commissioning tests provided ion saturation current values in the range assumed for the design, so the deduced plasma density estimate is consistent with the expected values.

Stable operation with control on magnetohydrodynamic modes has been obtained in the modified reversed field experiment employing a set of 192 feedback controlled saddle coils. Improvements of plasma temperature, confinement (twofold), and pulse length (threefold) and, as a consequence of the magnetic fluctuation reduction, strong mitigation of plasma-wall interaction and mode locking are reported.

Catheter balloon valvuloplasty of stenotic aortic valves has met with generally poor short- and long-term clinical results. Part of this problem resides with the lack of recognition of various etiologies of aortic stenosis. Part I of this review discusses the various etiologies of aortic stenosis and provides an anatomic basis for successful valve dilation. Results of an in vitro study indicate stenotic aortic valves are dilated by various mechanisms (cracking, stretching) based in part upon the etiology of the aortic valve stenosis.