Persimmon Leaf Flavonols Enhance the Anti-Cancer Effect of Heavy Ion Radiotherapy on Murine Xenograft Tumors

The cell cycle checkpoint system play a pivotal role in the cellular DNA damage response, and the discovery of checkpoint inhibitors is expected to sensitize current cancer therapies. Checkpoint signaling cascades are critically modulated by ATM (ataxia telangiectasia-mutated) and its related molecules. Generally, ATM primarily responds to ionizing irradiation-induced DNA double-strand breaks. Heavy ions from an accelerated carbon ion beam have been used to cure cancer because they are more effective than ionizing irradiation such as X-ray and γ-radiation in terms of biological damage. In a previous study, we demonstrated that a persimmon leaf flavonol (PLF) promoted the cytotoxic effect of chemotherapeutic agents on cancer cells through inhibition of checkpoint activities, especially in the ATM dependent pathway. The present study investigated whether PLF inhibits checkpoint activity during the DNA damage response induced by heavy ion irradiation. Treatment with PLF significantly increased the cytotoxicity of heavy ion irradiation in A549 adenocarcinoma cells. The phosphorylation of checkpoint proteins such as p53, SMC1, and Chk1 was increased by heavy ions. PLF reduced the phosphorylation of checkpoint proteins. Pre-treatment with PLF significantly prevented the decrease of mitotic cells in heavy ion-exposed cells. We further evaluated tumor volume in SCID mice inoculated with human lung adenocarcinoma A549 cells. The combination treatment of PLF and heavy ion resulted in a decrease of tumor volume compared with controls, although PLF itself did not exhibit any effect. These results indicate that PLF inhibits tumor growth through modulation of the DNA damage response. PLF may be useful for clinical application in combination with heavy ion radiotherapy.

Relativistic Heavy Ion Collider and the Large Hadron Collider for Heavy Ion Fusion

Heavy Ion Fusion makes use of the Relativistic Heavy Ion Collider at Brookhaven National Lab and the Large Hadron Collider in Geneva, Switzerland for Inertial Confinement Fusion. Two Storage Rings, which may or may not initially be needed, added to each of the Colliders increases the intensity of the Heavy Ion Beams making it comparable to the Total Energy delivered to the DT target by the National Ignition Facility at the Lawrence Livermore Lab. The basic Physics involved gives Heavy Ion Fusion an advantage over Laser Fusion because heavy ions have greater penetration power than photons. The Relativistic Heavy Ion Collider can be used as a Prototype Heavy Ion Fusion Reactor for the Large Hadron Collider.

Uniformity Control of Scanned Beam in 300 MeV Proton and Heavy Ion Accelerator Complex at SESRI

In recent years,heavy ion accelerator technology has been rapidly developing worldwide and widely applied in the fields of space radiation simulation and particle therapy.Usually,a very high uniformity in the irradiation area is required for the extracted ion beams,which is crucial because it directly affects the experimental precision and therapeutic effect.Specifically,ultra-large-area and high-uniformity scanning are crucial requirements for spacecraft radiation effects assessment and serve as core specification for beamline terminal design.In the 300 MeV proton and heavy ion accelerator complex at the Space Environment Simulation and Research Infrastructure(SESRI),proton and heavy ion beams will be accelerated and ultimately delivered to three irradiation terminals.In order to achieve the required large irradiation area of 320 mm×320 mm,horizontal and vertical scanning magnets are used in the extraction beam line.However,considering the various requirements for beam species and energies,the tracking accuracy of power supplies(PSs),the eddy current effect of scanning magnets,and the fluctuation of ion bunch structure will reduce the irradiation uniformity.To mitigate these effects,a beam uniformity optimization method based on the measured beam distribution was proposed and applied in the accelerator complex at SESRI.In the experiment,the uniformity is successfully optimized from 75%to over 90%after five iterations of adjustment to the PS waveforms.In this paper,the method and experimental results were introduced.

Experiment and simulation on degradation and burnout mechanisms of SiC MOSFET under heavy ion irradiation

Experiments and simulation studies on 283 MeV I ion induced single event effects of silicon carbide(SiC) metal–oxide–semiconductor field-effect transistors(MOSFETs) were carried out. When the cumulative irradiation fluence of the SiC MOSFET reached 5×10^(6)ion·cm^(-2), the drain–gate channel current increased under 200 V drain voltage, the drain–gate channel current and the drain–source channel current increased under 350 V drain voltage. The device occurred single event burnout under 800 V drain voltage, resulting in a complete loss of breakdown voltage. Combined with emission microscope, scanning electron microscope and focused ion beam analysis, the device with increased drain–gate channel current and drain–source channel current was found to have drain–gate channel current leakage point and local source metal melt, and the device with single event burnout was found to have local melting of its gate, source, epitaxial layer and substrate. Combining with Monte Carlo simulation and TCAD electrothermal simulation, it was found that the initial area of single event burnout might occur at the source–gate corner or the substrate–epitaxial interface, electric field and current density both affected the lattice temperature peak. The excessive lattice temperature during the irradiation process appeared at the local source contact, which led to the drain–source channel damage. And the excessive electric field appeared in the gate oxide layer, resulting in drain–gate channel damage.

Effect of temperature on heavy ion-induced single event transient on 16-nm FinFET inverter chains

The variations of single event transient(SET)pulse width of high-LET heavy ion irradiation in 16-nm-thick bulk silicon fin field-effect transistor(Fin FET)inverter chains with different driven strengths are measured at different temperatures.Three-dimensional(3D)technology computer-aided design simulations are carried out to study the SET pulse width and saturation current varying with temperature.Experimental and simulation results indicate that the increase in temperature will enhance the parasitic bipolar effect of bulk Fin FET technology,resulting in the increase of SET pulse width.On the other hand,the increase of inverter driven strength will change the layout topology,which has a complex influence on the SET temperature effects of Fin FET inverter chains.The experimental and simulation results show that the device with the strongest driven strength has the least dependence on temperature.

Investigation of heavy ion irradiation effects on a charge trapping memory capacitor by C-V measurement

Heavy ion irradiation effects on charge trapping memory(CTM)capacitors with TiN/Al_(2)O_(3)/HfO_(2)/Al_(2)O_(3)/HfO_(2)/SiO_(2)/p-Si structure have been investigated.The ion-induced interface charges and oxide trap charges were calculated and analyzed by capacitance-voltage(C-V)characteristics.The C-V curves shift towards the negative direction after swift heavy ion irradiation,due to the net positive charges accumulating in the trapping layer.The memory window decreases with the increase of ion fluence at high voltage,which results from heavy ion-induced structural damage in the blocking layer.The mechanism of heavy ion irradiation effects on CTM capacitors is discussed in detail with energy band diagrams.The results may help to better understand the physical mechanism of heavy ion-induced degradation of CTM capacitors.

Fuel compression in the magnetized cylindrical implosion driven by a gold tube heated by heavy ion beams

A magnetized cylindrical target composed of a gold tube filled with deuterium-tritium fuel plasma at low density is studied numerically in the present paper.A shock wave is produced when a heavy ion beam heats the gold along the direction of the magnetic field.The density peak of the shock wave increases with the increase in time and it propagates in the-r direction in the cylindrical tube.It seems that this wave is the supermagnetosonic wave.It is found that the Mach number M is between 6.96 and 19.19.The density peak of the shock wave increases as the intensity of the heavy ion beam increases.Furthermore,the density peak of the shock wave increases as the external magnetic field increases.

PhaseⅠ/Ⅱtrial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma

Background: After deinitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma(NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present signiicant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can beneit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy(IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radioresistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy(CIRT). In addition, CIRT is a high linear energy transfer(LET) radiation and provides an increased relative biological efectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 Gy E(gray equivalent), at 2.5 Gy E per daily fraction, was well tolerated in patients who were previously treated for NPC with a deinitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can beneit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the beneits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and design: The maximal tolerated dose(MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 Gy E(2.5 Gy E × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Eicacy in terms of overall survival(OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.Conclusions: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate eicacy but causes potentially severe toxicities. Improved outcomes in terms of eicacy and toxicity proile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.

Carbon ion radiotherapy for synchronous choroidal melanoma and lung cancer: A case report

BACKGROUND Despite being the most common intraocular malignancy among adults,choroidal melanoma is a rare cancer type,even more so when accompanied by lung cancer.We report a patient with synchronous choroid melanoma and lung cancer treated with carbon ion radiotherapy(CIRT).CASE SUMMARY A 41-year-old woman was transferred to our center with a diagnosis of choroidal melanoma in her right eye.During the examination,we found a right lung tumor that was histologically diagnosed as lung cancer.The patient was treated with CIRT for both malignant neoplasms.The CIRT dose was 70 photon equivalent doses(GyE)in five fractions for the right eye choroidal melanoma and 72 GyE in 16 fractions for the right lung cancer.At 3 mo after CIRT,the choroidal melanoma completely disappeared,as did the right lung cancer 7 mo after;the patient was in complete remission.CONCLUSION CIRT may be an effective treatment for double primary lung cancer and choroid melanoma.

Carbon ion radiotherapy for bladder cancer: A case report

BACKGROUND Radical cystectomy is considered the first choice for the treatment of muscleinvasive bladder cancer.However,for some patients who have lost the indications for surgery,external beam radiotherapy is a non-invasive and effective treatment.CASE SUMMARY A 76-year-old patient with bladder cancer who had serious comorbidities and could not tolerate surgery or chemotherapy came to the Wuwei Heavy Ion Center.He received carbon ion radiotherapy(CIRT)with a whole-bladder dose of 44 GyE and tumor boost of 20 GyE.When he finished CIRT,his bladder cancer-related hematuria completely disappeared,and computed tomography examination showed that the tumor had obviously decreased in size.At the 3-mo follow-up,the tumor disappeared,and there were no acute or late adverse events.CIRT was well tolerated in this patient.CONCLUSION CIRT may allow for avoiding resection and was well tolerated with curative outcomes.

Degradation of β-Ga_(2)O_(3) Schottky barrier diode under swift heavy ion irradiation

The electrical characteristics and microstructures ofβ-Ga_(2)O_(3) Schottky barrier diode(SBD)devices irradiated with swift heavy ions(2096 MeV Ta ions)have been studied.It was found thatβ-Ga_(2)O_(3) SBD devices showed the reliability degradation after irradiation,including turn-on voltage Von,on-resistance Ron,ideality factor n,and the reverse leakage current density Jr.In addition,the carrier concentration of the drift layer was decreased significantly and the calculated carrier removal rates were 5×10^(6)-1.3×10^(7)cm^(-1).Latent tracks induced by swift heavy ions were observed visually in the wholeβ-Ga2O3 matrix.Furthermore,crystal structure of tracks was amorphized completely.The latent tracks induced by Ta ions bombardments were found to be the reason for the decrease in carrier mobility and carrier concentration.Eventually,these defects caused the degradation of electrical characteristics of the devices.In terms of the carrier removal rates,theβ-Ga_(2)O_(3) SBD devices were more sensitive to swift heavy ions irradiation than SiC and GaN devices.

Differential Proteomics Reveals the Potential Injury Mechanism Induced by Heavy Ion Radiation in Mice Ovaries

In the present study, we used a proteomics approach based on a two-dimensional electrophoresis （2-DE） reference map to investigate protein expression in the ovarian tissues of pubertal Swiss-Webster mice subjected to carbon ion radiation （CIR）. Among the identified proteins, ubiquitin carboxy-terminal hydrolase L1 （UCH-L1） is associated with the cell cycle[1] and that it influences proliferation in ovarian tissues. We analyzed the expression of UCH-L1 and the proliferation marker proliferation cell nuclear antigen （PCNA） following CIR using immunoblotting and immunofluorescence. The proteomics and biochemical results provide insight into the underlying mechanisms of CIR toxicity in ovarian tissues.

Raman spectrum study of graphite irradiated by swift heavy ions

Highly oriented pyrolytic graphites are irradiated with 40.5-Me V and 67.7-Me V ^112Sn-ions in a wide range of fluences： 1×10^11 ions/cm^2–1×10^14ions/cm^2. Raman spectra in the region between 1200 cm^-1 and 3500cm^-1 show that the disorder induced by Sn-ions increases with ion fluence increasing. However, for the same fluence, the amount of disorder is greater for 40.5-Me V Sn-ions than that observed for 67.7-Me V Sn-ions, even though the latter has a slightly higher value for electronic energy loss. This is explained by the ion velocity effect. Importantly, ～ 3-cm^-1frequency shift toward lower wavenumber for the D band and ～ 6-cm^-1 shift toward lower wavenumber for the 2D band are observed at a fluence of 1×10^14 ions/cm^2, which is consistent with the scenario of radiation-induced strain. The strain formation is interpreted in the context of inelastic thermal spike model, and the change of the 2D band shape at high ion fluence is explained by the accumulation of stacking faults of the graphene layers activated by radiation-induced strain around ion tracks. Moreover,the hexagonal structure around the ion tracks is observed by scanning tunneling microscopy, which confirms that the strains near the ion tracks locally cause electronic decoupling of neighboring graphene layers.

Irradiation effects of graphene and thin layer graphite induced by swift heavy ions

Graphene and thin graphite films deposited on SiO2/Si are irradiated by swift heavy ions(209Bi, 9.5 Me V/u) with the fluences in a range of 1011ions/cm2–1012ions/cm2 at room temperature. Both pristine and irradiated samples are investigated by Raman spectroscopy. For pristine graphite films, the 'blue shift' of 2D bond and the 'red shift' of G bond with the decrease of thickness are found in the Raman spectra. For both irradiated graphene and thin graphite films, the disorder-induced D peak and D' peak are detected at the fluence above a threshold Φth. The thinner the film, the lower the Φthis. In this work, the graphite films thicker than 60 nm reveal defect free via the absence of a D bond signal under the swift heavy ion irradiation till the fluence of 2.6 × 1012ions/cm2. For graphite films thinner than 6 nm, the area ratios between D peak and G peak increase sharply with reducing film thickness. It concludes that it is much easier to induce defects in thinner films than in thicker ones by swift heavy ions. The intensities of the D peak and D' peak increase with increasing ion fluence, which predicts the continuous impacting of swift heavy ions can lead to the increasing of defects in samples. Different defect types are detected in graphite films of different thickness values. The main defect types are discussed via the various intensity ratios between the D peak and D' peak(HD/HD).

Structural modification in swift heavy ion irradiated muscovite mica

Two-layer monoclinic （2M） muscovite mica sheets with a thickness of 12 μm are irradiated with Sn ions at room temperature with electronic energy loss （dE/dx）e of 14.7 keV/nm. The ion fiuence is varied between 1 ×10^11 and 1 ×10^13 ions/cm^2. Structural transition in irradiated mica is investigated by x-ray diffraction （XRD）. The main diffraction peaks shift to the high angles, and the inter-planar distance decreases due to swift heavy ion （SHI） irradiation. Dehydration takes place in mica during SHI irradiation and mica with one-layer monoclinic （1M） structure is thought to be generated in 2M mica after SHI irradiation. In addition, micro stress and damage cross section in irradiated mica are analyzed according to XRD data. High resolution transmission electron microscopy （HRTEM） is used on the irradiated mica to obtain the detailed information about the latent tracks and structural modifications directly. The latent track in mica presents an amorphous zone surrounded by strain contrast shell, which is associated with the residual stress in irradiated mica.

Lattice damage in InGaN induced by swift heavy ion irradiation

The microstructural responses of In_(0.32)Ga_(0.68)N and In_(0.9)Ga_(0.1)N films to 2.25 GeV Xe ion irradiation have been investigated using x-ray diffraction,Raman scattering,ion channeling and transmission electron microscopy.It was found that the In-rich In_(0.9)Ga_(0.1)N is more susceptible to irradiation than the Ga-rich In_(0.32)Ga_(0.68)N.Xe ion irradiation with a fluence of 7×10^(11)ions·cm^(-2)leads to little damage in In_(0.32)Ga_(0.68)N but an obvious lattice expansion in In_(0.9)Ga_(0.1)N.The level of lattice disorder in In_(0.9)Ga_(0.1)N increases after irradiation,due to the huge electronic energy deposition of the incident Xe ions.However,no Xe ion tracks were observed to be formed,which is attributed to the very high velocity of 2.25 Ge V Xe ions.Point defects and/or small defect clusters are probably the dominant defect type in Xe-irradiated In_(0.9)Ga_(0.1)N.

Evaluation of Patient-Specific Quality Assurance for Carbon Ion Radiotherapy Using Full Energy Scanning Method at QST Hospital

Purpose: Patient-specific QA (PSQA) measurements for carbon ion radiotherapy (CIRT) are critical components of processes designed to identify discrepancies between calculated and delivered doses. We report the results of PSQA conducted at the QST Hospital during the period from September 2017 to March 2018. Methods: We analyzed PSQA results for 1448 fields for 10 disease sites with various target volumes, target depths and number of energy layers. For the PSQA, all the planned beams were recalculated on a water phantom with treatment planning software. The recalculated dose distributions were compared with the measured distributions using a 2D ionization chamber array at three depths, including 95% of the area of the prescription dose. These recalculated dose distributions were evaluated using the 3%/3mm gamma index with a passing threshold of 90%. Results: The passing rates for prostate, head and neck, and bone and soft tissue were 96.8%, 99.3%, and 91.7%, respectively. Additionally, 94.7% of lung plans with low energy beams passed. Overall, the CIRT in the QST Hospital reached a high passing rate of more than 95%. Although the remaining 5% failed to pass, there was no dependence between measurement depth and disease sites in these failures. Conclusion: Using PSQA measurements, we confirmed consistency between the planned and delivered doses for CIRT using the full energy scanning method.

Unified Hydrodynamics and Pseudorapidity Distributions of Charged Particles Produced in Heavy Ion Collisions at Low Energies at RHIC

In the context of unified hydrodynamics, we discuss the pseudorapidity distributions of the charged particles produced in Au-Au and Cu-Cu collisions at the low RHIC energies of √SNN = 19.6 and 22.4 GeV, respectively. It is found that the unified hydrodynamics alone can give a good description to the experimental measurements. This is different from the collisions at the maximum RHIC energy of √SNN = 200 GeV or at LHC energy of √SNN= 2.76 TeV, in which the leading particles must be taken into account so that we can properly explain the experimental observations.

Momentum-Dependent Symmetry Potential from Nuclear Collective Flows in Heavy Ion Collisions at Intermediate Energies

Within the isospin-dependent quantum molecular dynamics model, we investigate the nuclear collective flows produced in semi-central 197 Au＋197 Au collisions at intermediate energies. The neutron proton differential flows and difference of neutron proton collective flows are sensitive to the momentum-dependent symmetry potential. This sensitivity is less affected by both the isoscalar part of nuclear equation of state and in-medium nucleon- nucleon cross sections. Moreover, this sensitivity becomes pronounced with increasing the rapidity cut.

Experimental verification of therapeutic doses for the superficially-placed tumor radiotherapy with heavy ions at HIRFL

Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80--100 MeV/u carbon ions supplied by the Heavy Ion Research Facility in Lanzhou （HIRFL） at the Institute of Modern Physics, Chinese Academy of Sciences since November, 2006. A passive irradiation system and a dose optimization method for radiotherapy with carbon-ion beams have been developed. Experimental verification of longitudinally therapeutic dose distributions was conducted under the condition of simulating patient treatment in the therapy terminal at HIRFL. The measured depth-dose distributions basically coincide with the expected ones. These results indicate that the irradiation system and the dose optimization method are effective in the ongoing carbon-ion radiotherapy for shallow-seated tumors at HIRFL.