Prompt gamma imaging of proton pencil beams at clinical dose rate.

In this work, we present experimental results of a prompt gamma camera for real-time proton beam range verification. The detection system features a pixelated Cerium doped lutetium based scintillation crystal, coupled to Silicon PhotoMultiplier arrays, read out by dedicated electronics. The prompt gamma camera uses a knife-edge slit collimator to produce a 1D projection of the beam path in the target on the scintillation detector. We designed the detector to provide high counting statistics and high photo-detection efficiency for prompt gamma rays of several MeV. The slit design favours the counting statistics and could be advantageous in terms of simplicity, reduced cost and limited footprint. We present the description of the realized gamma camera, as well as the results of the characterization of the camera itself in terms of imaging performance. We also present the results of experiments in which a polymethyl methacrylate phantom was irradiated with proton pencil beams in a proton therapy center. A tungsten slit collimator was used and prompt gamma rays were acquired in the 3-6 MeV energy range. The acquisitions were performed with the beam operated at 100 MeV, 160 MeV and 230 MeV, with beam currents at the nozzle exit of several nA. Measured prompt gamma profiles are consistent with the simulations and we reached a precision (2σ) in shift retrieval of 4 mm with 0.5 × 10(8), 1.4 × 10(8) and 3.4 × 10(8) protons at 100, 160 and 230 MeV, respectively. We conclude that the acquisition of prompt gamma profiles for in vivo range verification of proton beam with the developed gamma camera and a slit collimator is feasible in clinical conditions. The compact design of the camera allows its integration in a proton therapy treatment room and further studies will be undertaken to validate the use of this detection system during treatment of real patients.

Strong-interaction shifts and widths of kaonic helium isotopes.

The kaonic 3He and 4He [Formula: see text] transitions in gaseous targets were observed by the SIDDHARTA experiment. The X-ray energies of these transitions were measured with large-area silicon-drift detectors using the timing information of the [Formula: see text] pairs produced by the DAΦNE [Formula: see text] collider. The strong-interaction shifts and widths both of the kaonic 3He and 4He 2p states were determined, which are much smaller than the results obtained by the previous experiments. The "kaonic helium puzzle" (a discrepancy between theory and experiment) was now resolved.

Preliminary study of kaonic deuterium X-rays by the SIDDHARTA experiment at DAΦNE.

The study of the [Formula: see text] system at very low energies plays a key role for the understanding of the strong interaction between hadrons in the strangeness sector. At the DAΦNE electron-positron collider of Laboratori Nazionali di Frascati we studied kaonic atoms with [Formula: see text] and [Formula: see text], taking advantage of the low-energy charged kaons from Φ-mesons decaying nearly at rest. The SIDDHARTA experiment used X-ray spectroscopy of the kaonic atoms to determine the transition yields and the strong interaction induced shift and width of the lowest experimentally accessible level (1s for H and D and 2p for He). Shift and width are connected to the real and imaginary part of the scattering length. To disentangle the isospin dependent scattering lengths of the antikaon-nucleon interaction, measurements of [Formula: see text] and of [Formula: see text] are needed. We report here on an exploratory deuterium measurement, from which a limit for the yield of the K-series transitions was derived: [Formula: see text] and [Formula: see text] (CL 90%). Also, the upcoming SIDDHARTA-2 kaonic deuterium experiment is introduced.

Measurements of the strong-interaction widths of the kaonic (3)He and (4)He 2p levels.

The kaonic (3)He and (4)He X-rays emitted in the [Formula: see text] transitions were measured in the SIDDHARTA experiment. The widths of the kaonic (3)He and (4)He 2p states were determined to be [Formula: see text], and [Formula: see text], respectively. Both results are consistent with the theoretical predictions. The width of kaonic (4)He is much smaller than the value of [Formula: see text] determined by the experiments performed in the 70's and 80's, while the width of kaonic (3)He was determined for the first time.

Prompt gamma imaging with a slit camera for real-time range control in proton therapy.

Treatments delivered by proton therapy are affected by uncertainties on the range of the beam within the patient, requiring medical physicists to add safety margins on the penetration depth of the beam. To reduce these margins and deliver safer treatments, different projects are currently investigating real-time range control by imaging prompt gammas emitted along the proton tracks in the patient. This study reports on the feasibility, development and test of a new concept of prompt gamma camera using a slit collimator to obtain a one-dimensional projection of the beam path on a scintillation detector. This concept was optimized, using the Monte Carlo code MCNPX version 2.5.0, to select high energy photons correlated with the beam range and detect them with both high statistics and sufficient spatial resolution. To validate the Monte Carlo model, spectrometry measurements of secondary particles emitted by a PMMA target during proton irradiation at 160 MeV were realized. An excellent agreement with the simulations was observed when using subtraction methods to isolate the gammas in direct incidence. A first prototype slit camera using the HiCam gamma detector was consequently prepared and tested successfully at 100 and 160 MeV beam energies. Results confirmed the potential of this concept for real-time range monitoring with millimetre accuracy in pencil beam scanning mode for typical clinical conditions. If we neglect electronic dead times and rejection of detected events, the current solution with its collimator at 15 cm from the beam axis can achieve a 1-2 mm standard deviation on range estimation in a homogeneous PMMA target for numbers of protons that correspond to doses in water at the Bragg peak as low as 15 cGy at 100 MeV and 25 cGy at 160 MeV assuming pencil beams with a Gaussian profile of 5 mm sigma at target entrance.

First measurement of kaonic helium-3 X-rays.

The first observation of the kaonic (3)He 3d→2p transition was made, using slow K- mesons stopped in a gaseous (3)He target. The kaonic atom X-rays were detected with large-area silicon drift detectors using the timing information of the K+K- pairs of ϕ-meson decays produced by the DAΦNE e+e- collider. The strong interaction shift of the kaonic (3)He 2p state was determined to be -2±2(stat)±4(syst) eV.

The DRAGO gamma camera.

In this work, we present the results of the experimental characterization of the DRAGO (DRift detector Array-based Gamma camera for Oncology), a detection system developed for high-spatial resolution gamma-ray imaging. This camera is based on a monolithic array of 77 silicon drift detectors (SDDs), with a total active area of 6.7 cm(2), coupled to a single 5-mm-thick CsI(Tl) scintillator crystal. The use of an array of SDDs provides a high quantum efficiency for the detection of the scintillation light together with a very low electronics noise. A very compact detection module based on the use of integrated readout circuits was developed. The performances achieved in gamma-ray imaging using this camera are reported here. When imaging a 0.2 mm collimated (57)Co source (122 keV) over different points of the active area, a spatial resolution ranging from 0.25 to 0.5 mm was measured. The depth-of-interaction capability of the detector, thanks to the use of a Maximum Likelihood reconstruction algorithm, was also investigated by imaging a collimated beam tilted to an angle of 45 degrees with respect to the scintillator surface. Finally, the imager was characterized with in vivo measurements on mice, in a real preclinical environment.

Connexins as precocious markers and molecular targets for chemical and pharmacological agents in carcinogenesis.

Gap junctions, intercellular channels structured by the connexin protein family, have been implicated in the control of cell homeostasis, proliferation, differentiation and death. A loss of the gap junction intercellular communication and/or connexin dysfunction are typical features of cancer per se and have been associated with the effect of many carcinogens. Indeed, many early human neoplasia of various organs and human tumor cell lines exhibit deficient connexin-mediated communication expression mainly related, in a large number of observations, with an aberrant cytoplasmic localization of this membranous protein. Restoration of normal phenotype in transformed cells by restoration of exogenous connexin gave rise to the concept that connexins may act as tumor suppressors. However, the mechanisms by which connexins mediate such a tumor suppressor effect are multiple. They may result from: formation of functional channels; hemichannels or are directly associated with connexin expression. In addition, the literature shows that they may be dependent upon the cell type and the connexin type. In the present review, we analyze all these aspects of connexin/gap junction involvement in the carcinogenesis process, in human cancers and discuss the possibility of using connexins as potential anti-oncogenic targets for cancer chemoprevention and/or chemotherapy.

A proposed role for ZO-1 in targeting connexin 43 gap junctions to the endocytic pathway.

Gap junctions are intercellular channels organized in plaque that directly link adjacent cells. Connexins (Cx), the constitutive proteins of gap junctions are associated with several partner proteins (cytoskeletal, anchoring) which could participate in plaque formation and degradation. Coimmunoprecipitation and indirect immunofluorescence analyses showed that ZO-1, a tight junction-associated protein, was linked to Cx43 in the testis. By using gamma-hexachlorocyclohexane (HCH), known to induce gap junction endocytosis, we demonstrated that endocytosis increased Cx43/ZO-1 association within the cytoplasm of treated Sertoli cells. In control cells, the two proteins were present, as expected, at the plasma membrane level, but poorly colocalized. The increased intracytoplasmic Cx43/ZO-1 complex was associated with a shift towards increased levels of Cx43 P1 and P2 isoforms. The HCH induced Cx43 hyperphosphorylation was abolished by the ERK inhibitor PD98059 suggesting that this effect could be mediated through activation of the ERK pathway. These data strongly support a novel role for ZO-1 in the turnover of Cx43 during gap junction plaque endocytosis.

[Acute poisoning with carbon dioxide: report of 2 fatal cases]. / Intossicazione acuta da anidride carbonica: descrizione di due casi mortali.

BACKGROUND: Carbon dioxide (CO2), a very high density gas, tends to stratify at the lowest levels of the atmosphere. It can be produced by neutral geothermal emissions, fermentative processes or by human and industrial activity. When carbon dioxide concentrations rise to a very high level in a confined and poorly ventilated space, the anoxic hazard is a very important cause of severe accidents that can involve workers and rescuers. At CO2 levels higher than 20% there is a very high risk of a fatal accident, also considering the odourless feature of this gas. OBJECT: Two fatal accidents in workers are described which occurred during inspection of a concrete well, built as a part of sewerage network in a rural area. In the weeks after the accident, composition and concentration of gases inside the well were analysed. We also considered the influence of an organic fertilizer called "pollina" which was found on the ground around the concrete well, in order to ascertain whether fermentation could alter the gas composition inside the well. METHODS: Samples of air and water were collected in the well and samples of the organic fertilizer (pollina) on the ground surrounding the concrete well were also taken. Different quantities of organic fertilizer (pollina) with or without water were incubated in airtight glass bottles and placed in a dark room at 20 degrees C temperature; analysis of air inside the glass bottles was performed after 7 and 18 days of incubation. All the samples of air and water were analysed by gas-chromatographic-mass-spectrometry. RESULTS: Analysis of the air samples collected inside the well after 2, 16 and 18 weeks after the accident showed a low concentration of O2 (range 4.2-9%), a high concentration of CO2 (range 5.9-12.3%), a normal level of N2 (range 78-85%) and a concentration of N2O between 0.03 and 0.19%. In water collected 2 weeks after the accident at the bottom of the concrete well, CO2 and N2O concentrations of respectively 222 mg/L and 2 mg/L were measured. In the bottles with "pollina" we found, at different times of incubation, high concentrations of CO2 (highest value 25.2%), low levels of O2 (lowest value 0.5%) and negligible concentrations of N2O (< 0.015%). CONCLUSIONS: All these findings suggest that the atmosphere inside the concrete well was altered by the fermentative processes of pollina. The death of the two workers, caused by a poorly oxygenated atmosphere with a high concentration of carbon dioxide, can be classified under the confined space hypoxic syndrome (CSHS).

High-Resolution High-Count-Rate X-ray Spectroscopy with State-of-the-Art Silicon Detectors.

For the European X-ray multi-mirror (XMM) satellite mission and the German X-ray satellite ABRIXAS, fully depleted pn-CCDs have been fabricated, enabling high-speed low-noise position-resolving X-ray spectroscopy. The detector was designed and fabricated with a homogeneously sensitive area of 36 cm(2). At 150 K it has a noise of 4 e(-) r.m.s., with a readout time of the total focal plane array of 4 ms. The maximum count rate for single-photon counting was 10(5) counts s(-1) under flat-field conditions. In the integration mode more than 10(9) counts s(-1) can be detected at 6 keV. Its position resolution is of the order of 100 micro m. The quantum efficiency is higher than 90% from carbon K X-rays (277 eV) up to 10 keV. New cylindrical silicon drift detectors have been designed, fabricated and tested. They comprise an integrated on-chip amplifier system with continuous reset, on-chip voltage divider, electron accumulation layer stabilizer, large area, homogeneous radiation entrance window and a drain for surface-generated leakage current. At count rates as high as 2 x 10(6) counts cm(-2) s(-1), they still show excellent spectroscopic behaviour at room-temperature operation in single-photon detection mode. The energy resolution at room temperature is 220 eV at 6 keV X-ray energy and 140 eV at 253 K, being achieved with Peltier coolers. These systems were operated at synchrotron light sources (ESRF, HASYLAB and NLS) as X-ray fluorescence spectrometers in scanning electron microscopes and as ultra low noise photodiodes. The operation of a multi-channel silicon drift detector system is already foreseen at synchrotron light sources for X-ray holography experiments. All systems are fabricated in planar technology having the detector and amplifiers monolithically integrated on high-resistivity silicon.

All-optical induction of noncentrosymmetry in a transparent nonlinear polymer rod.

What is believed to be the first evidence of an all-optical orientation of a highly transparent polymer is presented. The samples are bulk rods of poly(methyl methacrylate) grafted with paranitroaniline (PNA) obtained by use of copolymerization of methyl methacrylate (MMA) monomers mixed with grafted MMA-PNA monomers. Bulk samples were obtained after molding and polishing of the copolymer with standard techniques. Experiments show that the photoinduced second-order(1) susceptibility chi((2)) may occur through molecular reorientation following selective polar excitation of the nonlinear chromophores by simultaneous two- and three-photon absorption on the same electronic level.

Silicon drift detectors with on-chip electronics for x-ray spectroscopy.

The silicon drift detector (SDD) is a semiconductor device based on high resistivity silicon fully depleted through junctions implanted on both sides of the semiconductor wafer. The electrons generated by the ionizing radiation are driven by means of a suitable electric field from the point of interaction toward a collecting anode of small capacitance, independent of the active area of the detector. A suitably designed front-end JFET has been directly integrated on the detector chip close to the anode region, in order to obtain a nearly ideal capacitive matching between detector and transistor and to minimize the stray capacitances of the connections. This feature allows it to reach high energy resolution also at high count rates and near room temperature. The present work describes the structure and the performance of SDDs specially designed for high resolution spectroscopy with soft x rays at high detection rate. Experimental results of SDDs used in spectroscopy applications are also reported.