Mathematical analysis of FLASH effect models based on theoretical hypotheses.

OBJECTIVE: Clinical applications of FLASH radiotherapy require formulas to describe how the FLASH radiation features and other related factors determine the FLASH effect. Mathematical analysis of the models can connect the theoretical hypotheses with the radiobiological effect, which provides the foundation for establishing clinical application models. Moreover, experimental and clinical data can be used to explore the key factors through mathematical analysis. Approach: We abstract the complex models of the oxygen depletion hypothesis and radical recombination-antioxidants hypothesis into concise mathematical equations. The equations are solved to analyze how the radiation features and other factors influence the FLASH effect. Then we propose methodologies for determining the parameters in the models and utilizing the models to predict the FLASH effect. Main results: The formulas linking the physical, chemical and biological factors to the FLASH effect are obtained through mathematical derivation of the equation. The analysis indicates that the initial oxygen concentration, radiolytic oxygen consumption and oxygen recovery are key factors for the oxygen depletion hypothesis and that the level of antioxidants is the key factor for the radical recombination-antioxidants hypothesis. According to the model derivations and analysis, the methodologies for determining parameters and predicting the FLASH effect are proposed: the criteria for data filtration; the strategy of hybrid FLASH and conventional dose rate (CONV) irradiation to ensure the acquisition of effective experimental data across a wide dose range; pipelines of fitting parameters and predicting the FLASH effect. Significance: This study establishes the quantitative relationship between the FLASH effect and key factors. The derived formulas can be used to calculate the FLASH effect in future clinical FLASH radiotherapy. The proposed methodologies guide to obtain sufficient high-quality datasets and utilize them to predict FLASH effect. Furthermore, this study indicates the key factors of FLASH effect and offers clues to further explore the FLASH mechanism.

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives.

Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.

Harnessing innate immune pathways for therapeutic advancement in cancer.

The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

THUBreast: an open-source breast phantom generation software for x-ray imaging and dosimetry.

Objective. Establishing realistic phantoms of human anatomy is a continuing concern within virtual clinical trials of breast x-ray imaging. However, little attention has been paid to glandular distribution within these phantoms. The principal objective of this study was to develop breast phantoms considering the clinical glandular distribution.Approach. This research introduces an innovative method for integrating glandular distribution information into breast phantoms. We have developed an open-source software, THUBreast44http://github.com/true02Hydrogen/THUBreast/, which generates breast phantoms that accurately replicate both the structural texture and glandular distribution, two crucial elements in breast x-ray imaging and dosimetry. To validate the efficacy of THUBreast, we assembled three groups of breast phantoms (THUBreast, patient-based, homogeneous) for irradiation simulation and calculated the power-law exponents (ß) and mean glandular dose (Dg), indicators of texture realism and radiation risk, respectively, utilizing MC-GPU.Main results. Upon the computation of theDgfor the THUBreast phantoms, it was found to be in agreement with that absorbed by the phantoms based on patients, with an average deviation of 4%. The estimates of averageDgthus obtained were on average 23% less than those computed for the homogeneous phantoms. It was observed that the homogeneous phantoms did overestimate the averageDgby 30% when compared to the phantoms based on patients. The mean value ofßfor the images of THUBreast phantoms was found to be 2.92 ± 0.08, which shows a commendable agreement with the findings of prior investigations.Significance. It is evidently clear from the results that THUBreast phantoms have a preliminary good performance in both imaging and dosimetry in terms of indicators of texture realism and glandular dose. THUBreast represents a further step towards developing a powerful toolkit for comprehensive evaluation of image quality and radiation risk.

Computational model of radiation oxygen effect with Monte Carlo simulation: effects of antioxidants and peroxyl radicals.

PURPOSE: Oxygen plays a crucial role in radiation biology. Antioxidants and peroxyl radicals affect the oxygen effect greatly. This study aims to establish a computational model of the oxygen effect and explore the effect attributed to antioxidants and peroxyl radicals. MATERIALS AND METHODS: Oxygen-related reactions are added to our track-structure Monte Carlo code NASIC, including oxygen fixation, chemical repair by antioxidants and damage migration from base-derived peroxyl radicals. Then the code is used to simulate the DNA damage under various oxygen, antioxidant and damage migration rate conditions. The oxygen enhancement ratio(OER) is calculated quantifying by the number of double-strand breaks for each condition. The roles of antioxidants and peroxyl radicals are examined by manipulating the relevant parameters. RESULTS AND CONCLUSIONS: Our results indicate that antioxidants are capable of rapidly restoring DNA radicals through chemical reactions, which compete with natural and oxygen fixation processes. Additionally, antioxidants can react with peroxyl radicals derived from bases, thereby preventing the damage from migrating to DNA strands. By quantitatively accounting for the impact of peroxyl radicals and antioxidants on the OER curves, our study establishes a more precise and comprehensive model of the radiation oxygen effect.

Comprehensive characterization of MUC16 mutations in lung adenocarcinoma for immunotherapies and prognosis: An observational study.

Lung adenocarcinoma (LUAD) is a non-small-cell lung cancer and is the leading cause of cancer-related deaths worldwide. Immunotherapy is a promising candidate for LUAD, and tumor mutation burden (TMB) could be a new biomarker to monitor the response of cancer patients to immunotherapy. It is known that the mucin 16 (MUC16) mutation is the most common and affects the progression and prognosis of several cancers. However, whether MUC16 mutations are associated with TMB and tumor-infiltrating immune cells in LUAD is not fully elucidated. All the data were obtained from the cancer genome atlas database to assess the prognostic value and potential mechanism of MUC16 in LUAD. An immune prognostic model (IPM) was developed based on immune-related genes that could be differentially expressed between MUC16MUT and MUC16WT LUAD patients. Later, the IPM effect on the prognosis and immunotherapy of LUAD was comprehensively evaluated. MUC16 was frequently mutated in LUAD, with a mutational frequency of 43.4%, significantly associated with higher TMB and better clinical prognosis. Based on 436 patients with LUAD, an IPM was established and validated to differentiate patients with a low or high risk of poor survival. The univariate and multivariate Cox regression analyses demonstrated that the IPM was an independent prognostic indicator for LUAD patients. Elevated expressions of PD-L1, LAG3, PDCD1, and SIGLEC15, and most of the T-effector and interferon-γ gene signatures, were depicted in the high-risk group. Moreover, the nomogram using the IPM and clinical prognostic factors also predicted the overall survival and clinical utility. Our project developed a robust risk signature depending on the MUC16 status and provided novel insights for individualized treatment options for LUAD patients.

Comprehensive analysis identifies DNA damage repair-related gene HCLS1 associated with good prognosis in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-associated mortality. Lung adenocarcinoma (LUAD) amounts to more than 40% of all lung malignancies. Therefore, developing clinically useful biomarkers for this disease is critical. DNA damage repair (DDR) is a complicated signal transduction process that ensures genomic stability. DDR should be comprehensively analyzed to elucidate their clinical significance and tumor immune microenvironment interactions. Methods: In this study, DDR-related genes (DRGs) were selected to investigate their prognostic impact on LUAD. A regression-based prognostic model was established based on The Cancer Genome Atlas (TCGA)-LUAD cohort and three external Gene Expression Omnibus (GEO) validation cohorts (GSE31210, GSE68465, and GSE72094). The robust, established model could independently predict the clinical outcomes in patients. Then, the prognostic performance of risk profiles was assessed using a time-dependent receiver operating characteristic (ROC) curve, Cox regression, nomogram, and Kaplan-Meier analyses. Furthermore, the potential biological functions and infiltration status of DRGs in LUAD were investigated with ESTIMATE and CIBERSORT. Finally, the effects of HCLS1 on the clinical features, prognosis, biological function, immune infiltration, and treatment response in LUAD were systematically analyzed. Results: Eleven DRGs were constructed to categorize patients into high- and low-risk groups. The risk score was an independent predictor of overall survival (OS). HCLS1 expression was downregulated in LUAD samples and linked with clinicopathological features. Multivariate Cox regression analysis using the Kaplan-Meier plotter revealed that low HCLS1 expression was independently associated with poor OS. Moreover, the HCLS1 high-expression group had higher immune-related gene expression and ESTIMATE scores. It was positively correlated with the infiltration of M1 macrophages, activated memory CD4 T cells, CD8 T cells, memory B cells, resting dendritic cells, and memory CD4 T cells, Tregs, and neutrophils. Conclusions: A new classification system was developed for LUAD according to DDR characteristics. This stratification has important clinical values, reliable prognosis, and immunotherapy in patients with LUAD. Moreover, HCLS1 is a potential prognostic biomarker of LUAD that correlates with the extent of immune cell infiltration in the tumor microenvironment (TME).

In silico analysis reveals PRR11 as a prognostic and oncogenic marker in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common lung cancer. Although there are various treatments for LUAD, its prognosis remains poor. Therefore, it is imperative to identify new targets and develop novel therapeutic strategies. In this study, we analyze the expression of proline rich 11 (PRR11) in pan cancer based on The Cancer Genome Atlas (TCGA) database, and explore the prognostic value of PRR11 in LUAD by GEPIA2 (Gene Expression Profiling Interactive Analysis, version 2) database. In addition, the relationship between PRR11 and the clinicopathological features of LUAD was analyzed using UALCAN database. The association between PRR11 expression and immune infiltration was accessed. The PRR11 related genes were screened using LinkOmics and GEPIA2. Gene Ontology Term Enrichment (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed by David database. The results suggested that the expression of PRR11 in most tumor tissues was significantly higher than that in normal tissues. In LUAD patients, high expression of PRR11 was associated with shortened first progression survival (FPS), overall survival (OS) and post progression survival (PPS), and correlated with individual cancer stage, race, gender, smoking habit, and tissue subtype. Besides, the high expression of PRR11 was accompanied by a relatively higher infiltration level of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cell (MDSC), and decreased infiltration level of CD8+ T cells in the tumor microenvironment. GO analyses showed that PRR11 participated in biological processes such as cell division and cell cycle, and was involved in protein binding and microtubule binding functions. KEGG analyses revealed that PRR11 was implicated in p53 signaling pathway. All the results indicated that PRR11 might be an independent prognostic biomarker and therapeutic target for LUAD.

Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.

Development of a compact linear accelerator to generate ultrahigh dose rate high-energy X-rays for FLASH radiotherapy applications.

PURPOSE: In recent years, the FLASH effect, in which ultrahigh dose rate (UHDR) radiotherapy (RT) can significantly reduce toxicity to normal tissue while maintaining antitumor efficacy, has been verified in many studies and even applied in human clinical cases. This work evaluates whether a room-temperature radio-frequency (RF) linear accelerator (linac) system can produce UHDR high-energy X-rays exceeding a dose rate of 40 Gy/s at a clinical source-surface distance (SSD), exploring the possibility of a compact and economical clinical FLASH RT machine suitable for most hospital treatmentrooms. METHODS: A 1.65 m long S-band backward-traveling-wave (BTW) electron linac was developed to generate high-current electron beams, supplied by a commercial klystron-based power source. A tungsten-copper electron-to-photon conversion target for UHDR X-rays was designed and optimized with Monte Carlo (MC) simulations using Geant4 and thermal finite element analysis (FEA) simulations using ANSYS. EBT3 and EBT-XD radiochromic films, which were calibrated with a clinical machine Varian VitalBeam, were used for absolute dose measurements. A PTW ionization chamber detector was used to measure the relative total dose and a plane-parallel ionization chamber detector was used to measure the relative normalized dose of each pulse. RESULTS: The BTW linac generated 300-mA-pulse-current 11 MeV electron beams with 29 kW mean beam power, and the conversion target could sustain this high beam power within a maximum irradiation duration of 0.75 s. The mean energy of the produced X-rays was 1.66 MeV in the MC simulation. The measured flat-filter-free (FFF) maximum mean dose rate of the room-temperature linac exceeded 80 Gy/s at an SSD of 50 cm and 45 Gy/s at an SSD of 67.9 cm, both at a 2.1 cm depth of the water phantom. The FFF radiation fields at 50 cm and 67.9 cm SSD at a 2.1 cm depth of the water phantom showed Gaussian-like distributions with 14.3 and 20 cm full-width at half-maximum (FWHM) values, respectively. CONCLUSION: This work demonstrated the feasibility of UHDR X-rays produced by a room-temperature RF linac, and explored the further optimization of system stability. It shows that a simple and compact UHDR X-ray solution can be facilitated for both FLASH-RT scientific research and clinical applications.

Radical recombination and antioxidants: a hypothesis on the FLASH effect mechanism.

PURPOSE: FLASH (ultra-high dose rate) radiotherapy spares normal tissue while keeping tumor control. However, the mechanism of the FLASH effect remains unclear and may have consequences beyond the irradiated area. MATERIALS AND METHODS: We reanalyze the available results of ultra-high-dose-rate-related experiments to find out the key points of the mechanism of the FLASH effect. Then, we present a hypothesis on the mechanism of the FLASH effect: FLASH beams generate a high transient concentration of peroxyl radicals leading to a high fraction of radical recombination, which results in less oxidation damage to normal tissue. For the cells containing higher concentrations of antioxidants, the fractions of radical recombination are smaller because the antioxidants compete to react with peroxyl radicals. Therefore the damages by different dose rate beams differ slightly in this condition. Since some tumors contain a higher level of antioxidants, this may be the reason for the loss of the protective effect in tumors irradiated by FLASH beams. The high concentration of antioxidants in tumors results in slight radiolytic oxygen consumption, and consequently the protective effect observed in in vitro experiment cannot be observed in in vivo experiment. To quantitatively elaborate our hypothesis, a kinetic model is implemented to simulate the reactions induced by irradiation. Two parameters are defined to abstractly study the factors affecting the reaction, such as dose rate, antioxidants, total dose and reaction rate constants. RESULTS AND CONCLUSIONS: We find that the explanation of the difference between in vivo and in vitro experiments is crucial to understanding the mechanism of the FLASH effect. Our hypothesis agrees with the results of related experiments. Based on the kinetic model, the effects of these factors on the FLASH effect are quantitatively investigated.

Pan-cancer analysis reveals DDX21 as a potential biomarker for the prognosis of multiple tumor types.

Background: DExD-box helicase 21 (DDX21) is an essential member of the RNA helicase family. DDX21 is involved in the carcinogenesis of various malignancies, but there has been no comprehensive research on its involvement in different types of cancer. Method: This study used TCGA, CPTAC, GTEx, GEO, FANTOM5, BioGRID, TIMER2, GEPIA2, cBioPortal, STRING, and Metascape databases and Survival ROC software to evaluate DDX21 gene expression, protein expression, immunohistochemistry, gene mutation, immune infiltration, and protein phosphorylation in 33 TCGA tumor types, as well as the prognostic relationship between DDX21 and different tumors, by survival analysis and similar gene enrichment analysis. Furthermore, Cell Counting Kit-8 (CCK-8) and Transwell studies were employed to assess the effect of DDX21 expression on lung adenocarcinoma (LUAD) cell proliferation and migration. Result: The DDX21 gene was highly expressed in most cancers, and overexpression was associated with poor overall survival (OS) and disease-free survival (DFS). DDX21 mutations were most common in uterine corpus endometrial carcinoma (UCEC; >5%), and DDX21 expression was positively correlated with the degree of infiltration of CAF and CD8+ cells in several tumor types. Numerous genes were co-expressed with DDX21. Gene enrichment analysis revealed close links between DDX21, RNA metabolism, and ribosomal protein production. In vitro analysis of LUAD cells showed that DDX21 expression was positively correlated with cell proliferation and migration capacity, consistent with prior bioinformatics studies. Conclusions: DDX21 is overexpressed in a variety of cancers, and overexpression in some cancers is associated with poor prognosis. Immune infiltration and DDX21-related gene enrichment analyses indicated that DDX21 may affect cancer development through mechanisms that regulate tumor immunity, RNA metabolism, and ribosomal protein synthesis. This pan-cancer study revealed the prognostic value and the oncogenic role of DDX21.

Modeling of DNA Damage Repair and Cell Response in Relation to p53 System Exposed to Ionizing Radiation.

Repair of DNA damage induced by ionizing radiation plays an important role in the cell response to ionizing radiation. Radiation-induced DNA damage also activates the p53 system, which determines the fate of cells. The kinetics of repair, which is affected by the cell itself and the complexity of DNA damage, influences the cell response and fate via affecting the p53 system. To mechanistically study the influences of the cell response to different LET radiations, we introduce a new repair module and a p53 system model with NASIC, a Monte Carlo track structure code. The factors determining the kinetics of the double-strand break (DSB) repair are modeled, including the chromosome environment and complexity of DSB. The kinetics of DSB repair is modeled considering the resection-dependent and resection-independent compartments. The p53 system is modeled by simulating the interactions among genes and proteins. With this model, the cell responses to low- and high-LET irradiation are simulated, respectively. It is found that the kinetics of DSB repair greatly affects the cell fate and later biological effects. A large number of DSBs and a slow repair process lead to severe biological consequences. High-LET radiation induces more complex DSBs, which can be repaired by slow processes, subsequently resulting in a longer cycle arrest and, furthermore, apoptosis and more secreting of TGFß. The Monte Carlo track structure simulation with a more realistic repair module and the p53 system model developed in this study can expand the functions of the NASIC code in simulating mechanical radiobiological effects.

Synthesis of the Key Intermediate of SM-406 (Xevinapant) and Its Analogues.

Efficient methods for the synthesis of three dipeptide mimetics with diazabicycloalkanone amino acid scaffolds were developed. Among them, compound 3, which contains a 1,5-diazabicyclo[6,3,0]dodecanone amino acid core structure, was used as the key intermediate of a clinical staged IAP inhibitor SM-406 (Xevinapant). Compared with the reported methods for the synthesis of compound 3 and its derivatives, our method is more efficient and more suitable for large scale preparation.

Reassembling of albumin-bound paclitaxel mitigates myelosuppression and improves its antitumoral efficacy via neutrophil-mediated targeting drug delivery.

Albumin-bound paclitaxel (abPTX) has been widely used in cancer treatment. However, dose-related side effects, such as myelosuppression, restrict its clinical application. Cell-based targeting drug delivery is a promising way to mitigate systematic side-effects and improve antitumoral efficacy. In this study, we demonstrated that reassembled abPTX could be engulfed by neutrophils in vivo and delivered to tumor site, thus improving therapeutic efficacy and mitigating myelosuppression. First, in vitro analysis confirmed that reassembling of abPTX formed uniform and stable serum albumin nanoparticles (NP-abPTX) with size of 107.5 ± 2.29 nm and reserved the ability to kill tumor cells. Second, we found that NP-abPTX could be engulfed by activated neutrophil in vitro and in vivo but do not affect neutrophils' function, such as chemotaxis and activation. In a murine tumor model, we further proved that local radiotherapy (RT) induced inflammation activated peripheral neutrophils to capture venous infused NP-abPTX and carry them into tumor tissue. As compared to abPTX, infusion of NP-abPTX dramatically enhanced inhibition of tumor growth treated by local RT and mitigated hematotoxicity. Therefore, our study demonstrated a novel strategy to mitigate side-effects and to improve tumor killing efficacy of abPTX through neutrophil-mediated targeting drug delivery.

CPU-GPU coupling independent reaction times method in NASIC and application in water radiolysis by FLASH irradiation.

The mechanism of the FLASH effect remains unclear and could be revealed by studying chemical reactions during irradiation. Monte Carlo simulation of the radiolytic species is an effective tool to analyze chemical reactions, but the simulation is limited by computing costs of the step-by-step simulation of radiolytic species, especially when considering beam with complex time structure. The complexity of the time structure of beams from accelerators in FLASH radiotherapy requires a high-performance Monte Carlo code. In this work, we develop a CPU-GPU coupling accelerating code with the independent reaction times (IRT) method to extend the chemical module of our nanodosimetry Monte Carlo code NASIC. Every chemical molecule in the microenvironment contains time information to consider the reactions from different tracks and simulate beams with complex time structures. Performance test shows that our code significantly improved the computing efficiency of the chemical module by four orders of magnitude. Then the code is used to study the oxygen depletion hypothesis in FLASH radiotherapy for different conditions by setting different parameters. The transient oxygen consumption rate values in the water are calculated when the pulses width ranges from 2 ps to 2µs, the total dose ranges from 0.5 Gy to 100 Gy and the initial oxygen concentration ranges from 0.1% to 21%. The time evolution curves are simulated to study the effect of the time structure of an electron linear accelerator. Results show that the total dose in several microseconds is a better indicator reflecting the radiolytic oxygen consumption rate than the dose rate. The initial oxygen greatly affects the oxygen consumption rate because of the reaction competition. The diffusion of oxygen determined by the physiological parameters is the key factor affecting oxygen depletion during the radiation using electron linear accelerators. Our code provides an efficient tool for simulating water radiolysis in different conditions.

Adenovirus vaccine therapy with CD137L promotes CD8+ DCs-mediated multifunctional CD8+ T cell immunity and elicits potent anti-tumor activity.

Renal carcinoma progresses aggressively in patients with metastatic disease while curative strategies are limited. Here, we constructed a recombinant non-replicating adenovirus (Ad) vaccine encoding an immune activator, CD137L, and a tumor antigen, CAIX, for treating renal carcinoma. In a subcutaneous tumor model, tumor growth was significantly suppressed in the Ad-CD137L/CAIX vaccine group compared with the single vaccine group. The induction and maturity of CD11C+ and CD8+CD11C+ dendritic cell (DC) subsets were promoted in Ad-CD137L/CAIX co-immunized mice. Furthermore, the Ad-CD137L/CAIX vaccine elicited stronger tumor-specific multifunctional CD8+ T cell immune responses as demonstrated by increased proliferation and cytolytic function of CD8+ T cells. Notably, depletion of CD8+ T cells greatly compromised the effective protection provided by Ad-CD137L/CAIX vaccine, suggesting an irreplaceable role of CD8+ T cells for the immunopotency of the vaccine. In both lung metastatic and orthotopic models, Ad-CD137L/CAIX vaccine treatment significantly decreased tumor metastasis and progression and increased the induction of tumor-specific multifunctional CD8+ T cells, in contrast to treatment with the Ad-CAIX vaccine alone. The Ad-CD137L/CAIX vaccine also augmented the tumor-specific multifunctional CD8+ T cell immune response in both orthotopic and metastatic models. These results indicated that Ad-CD137L/CAIX vaccine elicited a potent anti-tumor activity by inducing CD8+DC-mediated multifunctional CD8+ T cell immune responses. The potential strategy of CD137L-based vaccine might be served as a novel treatment for renal carcinoma or other malignant tumors.

Development of Chinese mesh-type pediatric reference phantom series and application in dose assessment of Chinese undergoing computed tomography scanning.

Pediatric patients are in a growing stage with more dividing cells than adults. Therefore, they are more sensitive to the radiation dose when undergoing computed tomography (CT) scanning. It is necessary and essential to assess the organ absorbed dose and effective dose to children. Monte Carlo simulation with computational phantoms is one of the most used methods for dose calculation in medical imaging and radiotherapy. Because of the vast change of the pediatric body with age increasing, many research groups developed series pediatric phantoms for various ages. However, most of the existing pediatric reference phantoms were developed based on Caucasian populations, which is not conformable to Chinese pediatric patients. The use of different phantoms can contribute to a difference in the dose calculation. To assess the CT dose of Chinese pediatric patients more accurately, we developed the Chinese pediatric reference phantoms series, including the 3-month (CRC3m), 1-year-old (CRC01), 5-year-old (CRC05), 10-year-old (CRC10), 15-year-old male (CRCM15), and a 15-year-old female (CRCF15) phantoms. Furthermore, we applied them to dose assessment of patients undergoing CT scanning. The GE LightSpeed 16 CT scanner was simulated and the paper presents the detailed process of phantoms development and the establishment of the CT dose database (with x-ray tube voltages of 120, 100 and 80 kVp, with collimators of 20, 10, and 5 mm width, with filters for head and body), compares for the 1-year-old results with other results based on different phantoms and analyzes the CT dose calculation results. It was found that the difference in phantoms' characteristics, organ masses and positions had a significant impact on the CT dose calculation outcomes. For the 1-year-old phantom, the dose results of organs fully covered by the x-ray beam were within 10% difference from the results of other studies. For organs partially covered and not covered by the scan range, the maximum differences came up to 84% (stomach dose, chest examinations) and 463% (gonads dose, chest examinations) respectively. The findings are helpful for the dose optimization of Chinese pediatric patients undergoing CT scanning. The developed phantoms could be applied in dose estimation of other medical modalities.

A Newly Designed Seed-Loading Device for Verifying the Safety of 125I Implants to the Canine Carotid Artery.

A seed-loading device was designed and modeled using the Monte Carlo method to verify the biological effect of iodine-125 (125I) particles on blood vessels through animal experiments. The dose distribution characteristics of irradiated vessels were established by adjusting the design variables and geometry. The deviation between the actual value and the theoretical value was verified in vitro by the thermoluminescence dosimetry (TLD) method. After verification, the device was used to examine the biological effect of 125I irradiation of canine carotid arteries in two dogs (and one control dog) for 180 days. The hollow cylinder seed-loading device was constructed with an inner diameter of 0.5 cm and a length of 3.3 cm. When six seeds were loaded into a single layer, the source strength ratio of the intermediate layer to the edge layer was 0.7:1. When six layers of seeds were arranged at 0.45-cm intervals, the deviations between the maximum, minimum and mean energy fluence within 2.25 cm of the vessel wall were 2.19% and -4.12%, respectively, and -9% and 4%, respectively, when verified in vitro using TLD. The carotid arteries showed good tolerance to 0.56 kGy (range of 0.51-0.58 kGy) after 180 days of irradiation. In conclusion, this 125I seed-loading device overcomes the random distribution of seeds and lays an accurate radiophysical foundation for subsequent biological experiments. The preliminary results showed that the carotid artery has good tolerance to 0.56 kGy irradiation.

Composition of the bacterial community in the gastrointestinal tract of Kunming mice

Background: The intestinal bacterial community has an important role in maintaining human health. Dysbiosis is a key inducer of many chronic diseases including obesity and diabetes. Kunming mice are frequently used as a model of human disease and yet little is known about the bacterial microbiome resident to the gastrointestinal tract. Results: We undertook metagenomic sequencing of the luminal contents of the stomach, duodenum, jejunum, ileum, cecum, colon, and rectum of Kunming mice. Firmicutes was the dominant bacterial phylum of each intestinal tract and Lactobacillus the dominant genus. However, the bacterial composition differed among the seven intestinal tracts of Kunming mice. Compared with the small intestine, the large intestine bacterial community of Kunming mice is more stable and diverse. Conclusions: To our knowledge, ours is the first study to systematically describe the gastrointestinal bacterial composition of Kunming mice. Our findings provide a better understanding of the bacterial composition of Kunming mice and serves as a foundation for the study of precision medicine.