OSLD nanoDot characterization for carbon radiotherapy dosimetry.

Objective. This study characterized optically-stimulated luminescent dosimeter (OSLD) nanoDots for use in a therapeutic carbon beam using the Imaging and Radiation Oncology Core (IROC) framework for remote output verification.Approach. The absorbed dose correction factors for OSLD (fading, linearity, beam quality, angularity, and depletion), as defined by AAPM TG 191, were characterized for carbon beams. For the various correction factors, the effect of linear energy transfer (LET) was examined by characterizing in both a low and high LET setting.Main results. Fading was not statistically different between reference photons and carbon, nor between low and high LET beams; thus, the standard IROC-defined exponential function could be used to characterize fading. Dose linearity was characterized with a linear fit; while low and high LET carbon linearity was different, these differences were small and could be rolled into the uncertainty budget if using a single linearity correction. A linear fit between beam quality and dose-averaged LET was determined. The OSLD response at various angles of incidence was not statistically different, thus a correction factor need not be applied. There was a difference in depletion between low and high LET irradiations in a primary carbon beam, but this difference was small over the standard five readings. The largest uncertainty associated with the use of OSLDs in carbon was because of thekQcorrection factor, with an uncertainty of 6.0%. The overall uncertainty budget was 6.3% for standard irradiation conditions.Significance. OSLD nanoDot response was characterized in a therapeutic carbon beam. The uncertainty was larger than for traditional photon applications. These findings enable the use of OSLDs for carbon absorbed dose measurements, but with less accuracy than conventional OSLD audit programs.

Carbon dots as a novel photosensitizer for photodynamic therapy of cancer and bacterial infectious diseases: recent advances.

Carbon dots (CDs) are novel carbon-based nanomaterials that have been used as photosensitizer-mediated photodynamic therapy (PDT) in recent years due to their good photosensitizing activity. Photosensitizers (PSs) are main components of PDT that can produce large amounts of reactive oxygen species (ROS) when stimulated by light source, which have the advantages of low drug resistance and high therapeutic efficiency. CDs can generate ROS efficiently under irradiation and therefore have been extensively studied in disease local phototherapy. In tumor therapy, CDs can be used as PSs or PS carriers to participate in PDT and play an extremely important role. In bacterial infectious diseases, CDs exhibit high bactericidal activity as CDs are effective in disrupting bacterial cell membranes leading to bacterial death upon photoactivation. We focus on recent advances in the therapy of cancer and bacteria with CDs, and also briefly summarize the mechanisms and requirements for PSs in PDT of cancer, bacteria and other diseases. We also discuss the role CDs play in combination therapy and the potential for future applications against other pathogens.

Integrated application of transcriptomics and metabolomics provides insight into the mechanism of Eimeria tenella resistance to maduramycin.

Avian coccidiosis, caused by Eimeria parasites, continues to devastate the poultry industry and results in significant economic losses. Ionophore coccidiostats, such as maduramycin and monensin, are widely used for prophylaxis of coccidiosis in poultry. Nevertheless, their efficacy has been challenged by widespread drug resistance. However, the underlying mechanisms have not been revealed. Understanding the targets and resistance mechanisms to anticoccidials is critical to combat this major parasitic disease. In the present study, maduramycin-resistant (MRR) and drug-sensitive (DS) sporozoites of Eimeria tenella were purified for transcriptomic and metabolomic analysis. The transcriptome analysis revealed 5016 differentially expressed genes (DEGs) in MRR compared to DS, and KEGG pathway enrichment analysis indicated that DEGs were involved in spliceosome, carbon metabolism, glycolysis, and biosynthesis of amino acids. In the untargeted metabolomics assay, 297 differentially expressed metabolites (DEMs) were identified in MRR compared to DS, and KEGG pathway enrichment analysis indicated that these DEMs were involved in 10 pathways, including fructose and mannose metabolism, cysteine and methionine metabolism, arginine and proline metabolism, and glutathione metabolism. Targeted metabolomic analysis revealed 14 DEMs in MRR compared to DS, and KEGG pathway analysis indicated that these DEMs were involved in 20 pathways, including fructose and mannose metabolism, glycolysis/gluconeogenesis, and carbon metabolism. Compared to DS, energy homeostasis and amino acid metabolism were differentially regulated in MRR. Our results provide gene and metabolite expression landscapes of E. tenella following maduramycin induction. This study is the first work involving integrated transcriptomic and metabolomic analyses to identify the key pathways to understand the molecular and metabolic mechanisms underlying drug resistance to polyether ionophores in coccidia.

Targeting one-carbon metabolism for cancer immunotherapy.

BACKGROUND: One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune-related adverse events in patients. METHODS: We collected numerous literatures to explain the roles of one-carbon metabolism in cancer immunotherapy. RESULTS: In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future. CONCLUSION: Targeting one-carbon metabolism is useful for cancer immunotherapy.

Effects of cellular radioresponse on therapeutic helium-, carbon-, oxygen-, and neon-ion beams: a simulation study.

Objective. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges.Approach. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams.Main results. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases.Significance.From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.

Few-seconds range verification with short-lived positron emitters in carbon ion therapy.

In-beam PET (Positron Emission Tomography) is one of the most precise techniques for in-vivo range monitoring in hadron therapy. Our objective was to demonstrate the feasibility of a short irradiation run for range verification before a carbon-ion treatment. To do so a PMMA target was irradiated with a 220 MeV/u carbon-ion beam and annihilation coincidences from short-lived positron emitters were acquired after irradiations lasting 0.6 s. The experiments were performed at the synchrotron-based facility CNAO (Italian National Center of Oncological Hadrontherapy) by using the INSIDE in-beam PET detector. The results show that, with 3·107 carbon ions, the reconstructed positron emitting nuclei distribution is in good agreement with the predictions of a detailed FLUKA Monte Carlo study. Moreover, the radio-nuclei production is sufficiently abundant to determine the average ion beam range with a σ of 1 mm with a 6 s measurement of the activity distribution. Since the data were acquired when the beam was off, the proposed rapid calibration method can be applied to hadron beams extracted from accelerators with very different time structures.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.

BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660. RESULTS: DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. CONCLUSIONS: The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.

A new approach for the treatment of Alzheimer's disease: insulin-quantum dots.

The potential use of insulin supplementation for Alzheimer's Disease (AD) was aimed to investigate and explore CQDs as an alternative delivery system. CQDs were produced by microwave and characterised. Insulin-loaded Ins-CQDs and in-situ Gel-Ins-CQDs were developed. The in vitro release kinetics, penetrations of insulin through excised sheep nasal mucosa were determined. Toxicity of CQDs were calculated on SH-SY5Y cells. The stability and usability of the prepared formulations were assessed. The insulin release from the solution was 70.75% after 3 hours, while it was 37.51% for in-situ Gel-Ins-CQDs. IC50 value was 52 µM. The mean particle diameters of Ins-CQDs and in-situ Gel-Ins-CQDs varied between 8.35 ± 0.19 to 8.75 ± 0.03 nm during a 6-month period. Zeta potentials ranged from -31.51 ± 1.39 to -24.43 ± 0.26 mV, and PDI values were between 9.8 ± 0.01 to 5.3 ± 3.2%(SD, n = 3) for Ins-CQDs and in-situ Gel-Ins-CQDs, respectively.Our results show that Gel-Ins-CQDs represented a controlled release over time and can be used for AD through the nasal route.

Development and validation of MonteRay, a fast Monte Carlo dose engine for carbon ion beam radiotherapy.

BACKGROUND: Monte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; so far however, no commercial treatment planning system (TPS) provides a fast MC for supporting clinical practice in carbon ion therapy. PURPOSE: To extend and validate the in-house developed fast MC dose engine MonteRay for carbon ion therapy, including physical and biological dose calculation. METHODS: MonteRay is a CPU MC dose calculation engine written in C++ that is capable of simulating therapeutic proton, helium and carbon ion beams. In this work, development steps taken to include carbon ions in MonteRay are presented. Dose distributions computed with MonteRay are evaluated using a comprehensive validation dataset, including various measurements (pristine Bragg peaks, spread out Bragg peaks in water and behind an anthropomorphic phantom) and simulations of a patient plan. The latter includes both physical and biological dose comparisons. Runtimes of MonteRay were evaluated against those of FLUKA MC on a standard benchmark problem. RESULTS: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. In terms of pristine Bragg peaks, mean errors between simulated and measured integral depth dose distributions were between -2.3% and +2.7%. Comparing SOBPs at 5, 12.5 and 20 cm depth, mean absolute relative dose differences were 0.9%, 0.7% and 1.6% respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of 1.2 % ± 1.1 % $1.2\% \pm 1.1\;\%$ with global 3%/3 mm 3D-γ passing rates of 99.3%, comparable to those previously reached with FLUKA (98.9%). Comparisons against dose predictions computed with the clinical treatment planning tool RayStation 11B for a meningioma patient plan revealed excellent local 1%/1 mm 3D-γ passing rates of 98% for physical and 94% for biological dose. In terms of runtime, MonteRay achieved speedups against reference FLUKA simulations ranging from 14× to 72×, depending on the beam's energy and the step size chosen. CONCLUSIONS: Validations against clinical dosimetric measurements in homogeneous and heterogeneous scenarios and clinical TPS calculations have proven the validity of the physical models implemented in MonteRay. To conclude, MonteRay is viable as a fast secondary MC engine for supporting clinical practice in proton, helium and carbon ion radiotherapy.

Diamond based integrated detection system for dosimetric and microdosimetric characterization of radiotherapy ion beams.

BACKGROUND: Ion beam therapy allows for a substantial sparing of normal tissues and higher biological efficacy. Synthetic single crystal diamond is a very good material to produce high-spatial-resolution and highly radiation hard detectors for both dosimetry and microdosimetry in ion beam therapy. PURPOSE: The aim of this work is the design, fabrication and test of an integrated waterproof detector based on synthetic single crystal diamond able to simultaneously perform dosimetric and microdosimetric characterization of clinical ion beams. METHODS: The active elements of the integrated diamond device, that is, dosimeter and microdosimeter, were both realized in a Schottky diode configuration featured by different area, thickness, and shape by means of photolithography technologies for the selective growth of intrinsic and boron-doped CVD diamond. The cross-section of the sensitive volume of the dosimetric element is 4 mm2 and 1 µm-thick, while the microdosimetric one has an active cross-sectional area of 100 × 100 µm2 and a thickness of about 6.2 µm. The dosimetric and microdosimetric performance of the developed device was assessed at different depths in a water phantom at the MedAustron ion beam therapy facility using a monoenergetic uniformly scanned carbon ion beam of 284.7 MeV/u and proton beam of 148.7 MeV. The particle flux in the region of the microdosimeter was 6·107  cm2 /s for both irradiation fields. At each depth, dose and dose distributions in lineal energy were measured simultaneously and the dose mean lineal energy values were then calculated. Monte Carlo simulations were also carried out by using the GATE-Geant4 code to evaluate the relative dose, dose averaged linear energy transfer (LETd ), and microdosimetric spectra at various depths in water for the radiation fields used, by considering the contribution from the secondary particles generated in the ion interaction processes as well. RESULTS: Dosimetric and microdosimetric quantities were measured by the developed prototype with relatively low noise (∼2 keV/µm). A good agreement between the measured and simulated dose profiles was found, with discrepancies in the peak to plateau ratio of about 3% and 4% for proton and carbon ion beams respectively, showing a negligible LET dependence of the dosimetric element of the device. The microdosimetric spectra were validated with Monte Carlo simulations and a good agreement between the spectra shapes and positions was found. Dose mean lineal energy values were found to be in close agreement with those reported in the literature for clinical ion beams, showing a sharp increase along the Bragg curve, being also consistent with the calculated LETd for all depths within the experimental error of 10%. CONCLUSIONS: The experimental indicate that the proposed device can allow enhanced dosimetry in particle therapy centers, where the absorbed dose measurement is implemented by the microdosimetric characterization of the radiation field, thus providing complementary results. In addition, the proposed device allows for the reduction of the experimental uncertainties associated with detector positioning and could facilitate the partial overcoming of some drawbacks related to the low sensitivity of diamond microdosimeters to low LET radiation.

Beam delivery characteristics of the Hitachi carbon ion scanning system at Osaka Heavy Ion Medical Accelerator in Kansai (HIMAK).

BACKGROUND: Using the pencil beam raster scanning method employed at most carbon beam treatment facilities, spots can be moved without interrupting the beam, allowing for the delivery of a dose between spots (move dose). This technique is also known as Dose-Driven-Continuous-Scanning (DDCS). To minimize its impact on HIMAK patient dosimetry, there's an upper limit to the move dose. Spots within a layer are grouped into sets, or "break points," allowing continuous irradiation. The beam is turned off when transitioning between sets or at the end of a treatment layer or spill. The control system beam-off is accomplished by turning off the RF Knockout (RFKO) extraction and after a brief delay the High Speed Steering Magnet (HSST) redirects the beam transport away from isocenter to a beam dump. PURPOSE: The influence of the move dose and beam on/off control on the dose distribution and irradiation time was evaluated by measurements never before reported and modelled for Hitachi Carbon DDCS. METHOD: We conducted fixed-point and scanning irradiation experiments at three different energies, both with and without breakpoints. For fixed-point irradiation, we utilized a 2D array detector and an oscilloscope to measure beam intensity over time. The oscilloscope data enabled us to confirm beam-off and beam-on timing due to breakpoints, as well as the relative timing of the RFKO signal, HSST signal, and dose monitor (DM) signals. From these measurements, we analyzed and modelled the temporal characteristics of the beam intensity. We also developed a model for the spot shape and amplitude at isocenter occurring after the beam-off signal which we called flap dose and its dependence on beam intensity. In the case of scanning irradiation, we measured move doses using the 2D array detector and compared these measurements with our model. RESULT: We observed that the most dominant time variation of the beam intensity was at 1 kHz and its harmonic frequencies. Our findings revealed that the derived beam intensity cannot reach the preset beam intensity when each spot belongs to different breakpoints. The beam-off time due to breakpoints was approximately 100 ms, while the beam rise time and fall time (tdecay ) were remarkably fast, about 10 ms and 0.2 ms, respectively. Moreover, we measured the time lag (tdelay ) of approximately 0.2 ms between the RFKO and HSST signals. Since tdelay ≈ tdecay at HIMAK then the HSST is activated after the residual beam intensity, resulting in essentially zero flap dose at isocenter from the HSST. Our measurements of the move dose demonstrated excellent agreement with the modelled move dose. CONCLUSION: We conducted the first move dose measurement for a Hitachi Carbon synchrotron, and our findings, considering beam on/off control details, indicate that Hitachi's carbon synchrotron provides a stable beam at HIMAK. Our work suggests that measuring both move dose and flap dose should be part of the commissioning process and possibly using our model in the Treatment Planning System (TPS) for new facilities with treatment delivery control systems with higher beam intensities and faster beam-off control.

Monoclonal antibody-navigated carbon-encapsulated iron nanoparticles used for MRI-based tracking integrin receptors in murine melanoma.

Integrin beta-3 is a cell adhesion molecule that mediate cell-to-cell and cell-to-extracellular matrix communication. The major goal of this study was to explore melanoma cells (B16F10) based upon specific direct targeting of the ß3 subunit (CD61) in the integrin αvß3 receptor using carbon-encapsulated iron nanoparticles decorated with monoclonal antibodies (Fe@C-CONH-anti-CD61 and Fe@C-(CH2)2-CONH-anti-CD61). Both melanoma cells treated with nanoparticles as well as C57BL/6 mice bearing syngeneic B16-F10 tumors intravenously injected with nanoparticles were tested in preclinical MRI studies. The as-synthesized carbon-encapsulated iron nanoparticles functionalized with CD61 monoclonal antibodies have been successfully used as a novel targeted contrast agent for MRI-based tracking melanoma cells expressing the ß3 subunit of the integrin αvß3 receptor.

Mechanistic modelling of relative biological effectiveness of carbon ion beams and comparison with experiments.

Objective.Relative biological effectiveness (RBE) plays a vital role in carbon ion radiotherapy, which is a promising treatment method for reducing toxic effects on normal tissues and improving treatment efficacy. It is important to have an effective and precise way of obtaining RBE values to support clinical decisions. A method of calculating RBE from a mechanistic perspective is reported.Approach.Ratio of dose to obtain the same number of double strand breaks (DSBs) between different radiation types was used to evaluate RBE. Package gMicroMC was used to simulate DSB yields. The DSB inductions were then analyzed to calculate RBE. The RBE values were compared with experimental results.Main results.Furusawa's experiment yielded RBE values of 1.27, 2.22, 3.00 and 3.37 for carbon ion beam with dose-averaged LET of 30.3 keVµm-1, 54.5 keVµm-1, 88 keVµm-1and 137 keVµm-1, respectively. RBE values computed from gMicroMC simulations were 1.75, 2.22, 2.87 and 2.97. When it came to a more sophisticated carbon ion beam with 6 cm spread-out Bragg peak, RBE values were 1.61, 1.63, 2.19 and 2.36 for proximal, middle, distal and distal end part, respectively. Values simulated by gMicroMC were 1.50, 1.87, 2.19 and 2.34. The simulated results were in reasonable agreement with the experimental data.Significance.As a mechanistic way for the evaluation of RBE for carbon ion radiotherapy by combining the macroscopic simulation of energy spectrum and microscopic simulation of DNA damages, this work provides a promising tool for RBE calculation supporting clinical applications such as treatment planning.

Advances in Magnetic Carbon Dots: A Theranostics Platform for Fluorescence/Magnetic Resonance Bimodal Imaging and Therapy for Tumors.

Theranostics technology that combines tumor diagnosis or monitoring with therapy is an important direction for the future development of tumor treatment. It takes advantage of efficiently observing tumor tissues, monitoring tumor treatment in real time, and significantly improving the cure efficiency. Magnetic carbon dots (CDs) are of wide interest as molecular imaging probes, drug carriers, photosensitizers, and radiosensitizers in the integration of tumor fluorescence/magnetic resonance bimodal diagnosis and treatment because of their small size, good optical stability, magnetic relaxation rate, and biocompatibility. This review first analyzes and compares the synthesis methods and physicochemical properties of magnetic CDs in recent years and then concludes their mechanism in tumor fluorescence/magnetic resonance bimodal imaging and therapy in details. Subsequently, the research progress of their application in tumor theranostics are summarized. Finally, the problems and challenges of magnetic CDs for development at this stage are prospected. This review provides new ideas for their controlled synthesis and application in efficient and precise therapy for tumors.

A Concise Review of Carbon Dots and their Pharmaceutical and Biomedical Applications.

For the last two decades, carbon dots, a revolutionary type of carbon nanomaterial with less than 10 nm diameter, have attracted considerable research interest. CDs exhibit various physicochemical properties and favorable characteristics, including excellent water solubility, unique optical properties, low cost, eco-friendliness, an abundance of reactive surface groups, and high stability. As a result, the synthesis of CDs and their applications in pharmaceutical and related disciplines have received increasing interest. Since CDs are biocompatible and biodegradable with low toxicity, they are a promising healthcare tool. CDs are extensively employed for numerous applications to date, including theranostics, bioimaging, drug delivery, biosensing, gene delivery, cancer therapy, electrochemical biosensing, and inflammatory treatment. This comprehensive review aims to explore various synthesis methods of carbon dots, including top-down and bottom-up approaches, as well as highlight the characterization techniques employed to assess their physicochemical and biological properties. Additionally, the review delves into carbon dots' pharmaceutical and biomedical applications, showcasing their potential in drug delivery, bioimaging, diagnostics, and therapeutics.

Identification of Early Biochemical Recurrence Predictors in High-Risk Prostate Cancer Patients Treated with Carbon-Ion Radiotherapy and Androgen Deprivation Therapy.

The aim of this retrospective study was to identify clinical predictors of early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). A total of 670 high-risk PCa patients treated with CIRT and ADT were included in the study. Early BCR was defined as recurrence occurring during adjuvant ADT after CIRT or within 2 years after completion of ADT. Univariate and multivariate analyses were performed to identify clinical predictors of early BCR. Patients were also classified according to the Systemic Therapy in Advancing or Metastatic Prostate cancer (STAMPEDE) PCa classification. Early BCR was observed in 5.4% of the patients. Multivariate analysis identified clinical T3b stage and ≥75% positive biopsy cores as clinical predictors of early BCR after CIRT and ADT. The STAMPEDE PCa classification was also significantly associated with early BCR based on univariate analysis. These predictors can help clinicians identify patients who are at risk of early BCR. In the future, combination therapy of ADT with abiraterone may be an option for high-risk PCa patients who are at risk of early BCR, based on the results of the STAMPEDE study.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (Part 3): Chapter 3. Clinical research, Chapter 4. Future challenges, Chapter 5. Discussion, and Conclusion.

Clinical studies of ion beam therapy have been performed at the Lawrence Berkeley Laboratory (LBL), National Institute of Radiological Sciences (NIRS), Gesellschaft für Schwerionenforschung (GSI), and Deutsches Krebsforschungszentrum (DKFZ), in addition to the development of equipment, biophysical models, and treatment planning systems. Although cancers, including brain tumors and pancreatic cancer, have been treated with the Bevalac's neon-ion beam at the LBL (where the first clinical research was conducted), insufficient results were obtained owing to the limited availability of neon-ion beams and immaturity of related technologies. However, the 184-Inch Cyclotron's helium-ion beam yielded promising results for chordomas and chondrosarcomas at the base of the skull. Using carbon-ion beams, NIRS has conducted clinical trials for the treatment of common cancers for which radiotherapy is indicated. Because better results than X-ray therapy results have been obtained for lung, liver, pancreas, and prostate cancers, as well as pelvic recurrences of rectal cancer, the Japanese government recently approved the use of public medical insurance for carbon-ion radiotherapy, except for lung cancer. GSI obtained better results than LBL for bone and soft tissue tumors, owing to dose enhancement enabled by scanning irradiation. In addition, DKFZ compared treatment results of proton and carbon-ion radiotherapy for these tumors. This article summarizes a series of articles (Parts 1-3) and describes future issues of immune ion beam therapy and linear energy transfer optimization.

High-LET charged particles: radiobiology and application for new approaches in radiotherapy.

The number of patients treated with charged-particle radiotherapy as well as the number of treatment centers is increasing worldwide, particularly regarding protons. However, high-linear energy transfer (LET) particles, mainly carbon ions, are of special interest for application in radiotherapy, as their special physical features result in high precision and hence lower toxicity, and at the same time in increased efficiency in cell inactivation in the target region, i.e., the tumor. The radiobiology of high-LET particles differs with respect to DNA damage repair, cytogenetic damage, and cell death type, and their increased LET can tackle cells' resistance to hypoxia. Recent developments and perspectives, e.g., the return of high-LET particle therapy to the US with a center planned at Mayo clinics, the application of carbon ion radiotherapy using cost-reducing cyclotrons and the application of helium is foreseen to increase the interest in this type of radiotherapy. However, further preclinical research is needed to better understand the differential radiobiological mechanisms as opposed to photon radiotherapy, which will help to guide future clinical studies for optimal exploitation of high-LET particle therapy, in particular related to new concepts and innovative approaches. Herein, we summarize the basics and recent progress in high-LET particle radiobiology with a focus on carbon ions and discuss the implications of current knowledge for charged-particle radiotherapy. We emphasize the potential of high-LET particles with respect to immunogenicity and especially their combination with immunotherapy.

Deep learning-based fast denoising of Monte Carlo dose calculation in carbon ion radiotherapy.

BACKGROUND: Plan verification is one of the important steps of quality assurance (QA) in carbon ion radiotherapy. Conventional methods of plan verification are based on phantom measurement, which is labor-intensive and time-consuming. Although the plan verification method based on Monte Carlo (MC) simulation provides a more accurate modeling of the physics, it is also time-consuming when simulating with a large number of particles. Therefore, how to ensure the accuracy of simulation results while reducing simulation time is the current difficulty and focus. PURPOSE: The purpose of this work was to evaluate the feasibility of using deep learning-based MC denoising method to accelerate carbon-ion radiotherapy plan verification. METHODS: Three models, including CycleGAN, 3DUNet and GhostUNet with Ghost module, were used to denoise the 1 × 106 carbon ions-based MC dose distribution to the accuracy of 1 × 108 carbon ions-based dose distribution. The CycleGAN's generator, 3DUNet and GhostUNet were all derived from the 3DUNet network. A total of 59 cases including 29 patients with head-and-neck cancers and 30 patients with lung cancers were collected, and 48 cases were randomly selected as the training set of the CycleGAN network and six cases as the test set. For the 3DUNet and GhostUNet models, the numbers of training set, validation set, and test set were 47, 6, and 6, respectively. Finally, the three models were evaluated qualitatively and quantitatively using RMSE and three-dimensional gamma analysis (3 mm, 3%). RESULTS: The three end-to-end trained models could be used for denoising the 1 × 106 carbon ions-based dose distribution, and their generalization was proved. The GhostUNet obtained the lowest RMSE value of 0.075, indicating the smallest difference between its denoised and 1 × 108 carbon ions-based dose distributions. The average gamma passing rate (GPR) between the GhostUNet denoising-based versus 1 × 108 carbon ions-based dose distributions was 99.1%, higher than that of the CycleGAN at 94.3% and the 3DUNet at 96.2%. Among the three models, the GhostUNet model had the fewest parameters (4.27 million) and the shortest training time (99 s per epoch) but achieved the best denoising results. CONCLUSION: The end-to-end deep network GhostUNet outperforms the CycleGAN, 3DUNet models in denoising MC dose distributions for carbon ion radiotherapy. The network requires less than 5 s to denoise a sample of MC simulation with few particles to obtain a qualitative and quantitative result comparable to the dose distribution simulated by MC with relatively large number particles, offering a significant reduction in computation time.