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PURPOSE: The aim of the study was to compare the dose differences between two kinds of materials (silica gel and hydrogel) used to prepare boluses based on three-dimensional (3D) printing technologies and commercial bolus in head phantoms simulating nose, ear, and parotid gland radiotherapy. METHODS AND MATERIALS: We used 3D printing technology to make silica gel and hydrogel boluses. To evaluate the clinical feasibility, intensity modulated radiation therapy (IMRT) plans were created for head phantoms that were bolus-free or had a commercial bolus, a silica gel bolus, or a hydrogel bolus. Dosimetry differences were compared in simulating nose, ear, and parotid gland radiotherapy separately. RESULTS: The air gaps were smaller in the silica gel and hydrogel bolus than the commercial one. In nose plans, it was shown that the V95% (relative volume that is covered by at least 95% of the prescription dose) of the silica gel (99.86%) and hydrogel (99.95%) bolus were better than the commercial one (98.39%) and bolus-free (87.52%). Similarly, the homogeneity index (HI) and conformity index (CI) of the silica gel (0.06; 0.79) and hydrogel (0.058; 0.80) bolus were better than the commercial one (0.094; 0.72) and bolus-free (0.59; 0.53). The parameters of results (HI, CI, V95% ) were also better in 3D printing boluses than in the commercial bolus or without bolus in ear and parotid plans. CONCLUSIONS: Silica gel and hydrogel boluses were not only good for fit and a high level of comfort and repeatability, but also had better parameters in IMRT plans. They could replace the commercial bolus for clinical use.
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Hidrogéis/química , Imagens de Fantasmas , Fótons/uso terapêutico , Impressão Tridimensional/instrumentação , Planejamento da Radioterapia Assistida por Computador/métodos , Sílica Gel/química , Simulação por Computador , Neoplasias da Orelha/radioterapia , Cabeça/efeitos da radiação , Humanos , Neoplasias Nasais/radioterapia , Órgãos em Risco/efeitos da radiação , Neoplasias Parotídeas/radioterapia , Dosagem RadioterapêuticaRESUMO
VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.
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Antígenos B7 , Neoplasias , Humanos , Antígenos B7/química , Antígenos B7/metabolismo , Simulação de Acoplamento Molecular , Leucócitos Mononucleares/metabolismo , AnticorposRESUMO
Background: The immune system is well known to exert tumor immunosurveillance effects, and that immune cells circulating in the peripheral blood affect tumor prognosis. The study investigated the effect of estimated dose of radiation on circulating immune cells (EDRIC) and tumor control for esophageal cancer patients treated with concurrent chemo-radiotherapy. Materials and Methods: A total of 146 esophageal cancer patients treated with radiotherapy between January 2016 and June 2020 were retrospectively identified. We determined EDRIC, known prognostic factors, and the association of these factors with progression-free survival (PFS) and overall survival (OS). Results: The median follow-up was 17.9 months (2.7-60.4 months). The 3-year OS was 39.2%. Severe post-treatment lymphopenia was observed in 84.2% of patients. A negative correlation between EDRIC and absolute lymphocyte count was found (r = -0.679; p < 0.001). Patients with EDRIC ≥10.3 Gy were more likely to demonstrate grade 4 lymphopenia (55.2% vs. 4.5%; p < 0.001). Patients with grade 4 lymphopenia had a worse OS and PFS. On multivariate analysis, EDRIC was independently associated with OS (hazard ratio [HR], 1.142; p = 0.016) and PFS (HR, 1.121; p = 0.019). Conclusions: EDRIC can predict lymphocyte reduction and poor prognosis for esophageal cancer patients treated with radiotherapy.
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Neoplasias Esofágicas , Linfopenia , Humanos , Estudos Retrospectivos , Quimiorradioterapia/efeitos adversos , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Prognóstico , Linfopenia/etiologia , Linfopenia/tratamento farmacológico , Doses de RadiaçãoRESUMO
In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.
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Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.
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Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Antígeno B7-H1 , Receptor de Morte Celular Programada 1/metabolismo , Leucócitos Mononucleares/metabolismo , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.
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It is difficult to study the intestinal damage induced by space radiation to astronauts directly, and few prediction models exist. However, we can simulate it in patients with pelvic tumor radiotherapy (RT). Radiation-induced intestinal injury (RIII) is common in cancer patients who receieved pelvic and abdominal RT. We dynamically analyzed gut microbiota and metabolites alterations in 17 cervical and endometrial cancer patients after pelvic RT. In patients who later developed grade 2 RIII, dysbiosis of gut microbiota and metabolites were observed. Univariate analysis showed that Erysipelatoclostridium and ptilosteroid A were related to the occurrence of grade 2 RIII. Notably, a strong positive correlation between gut bacteria Erysipelatoclostridium relative abundance and gut metabolite ptilosteroid A expression was found. Furthermore, combinations of Erysipelatoclostridium and ptilosteroid A could provide good diagnostic markers for grade 2 RIII. In conclusion, gut bacteria Erysipelatoclostridium and its related metabolite ptilosteroid A may collaboratively predict RIII, and could be diagnostic biomarkers for RIII and space radiation injury.
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Microbioma Gastrointestinal , Lesões por Radiação , Bactérias , Disbiose/microbiologia , Humanos , PregnanosRESUMO
OBJECTIVE: Due to the influence of gravity, inertia and friction, there will be deviation between the position of multileaf collimator (MLC) in the delivered field and the initial intensity modulated radiotherapy (IMRT) plan. This study explores the effects of the fragmentation level of subfield sequences on this deviation and seeks ways to improve the accuracy of field delivery in IMRT for nasopharyngeal carcinoma (NPC). METHODS: 30 patients with NPC were selected, and two groups (groups A and B) of IMRT plans were made in Pinnacle planning system. Different planning parameters were used for optimization so that the subfield sequence fragmentation level of Group B was significantly lower than that of Group A. With the MapCheck2, verification plan was implemented in two ways: 0o gantry angle and the actual treatment angle, then the differences between the two verification results of each group plan were analyzed. RESULTS: The γ-passing rate verified at the actual treatment angle was lower than that of 0o gantry angle for each group plan, whereas the Group B plan shows small reduction. Mean change value (Δ) was decreased from 1.01% (Group A) to 0.40% (Group B) with 3%/3 mm criteria and 2.88% (Group A) to 1.52% (Group B) with 2%/2 mm criteria, respectively. The smaller the difference (Δ), the actual output dose of the field is more consistent with the original plan. There was no significant correlation between this change and the angle of the field. CONCLUSION: Appropriately reducing the fragmentation level of subfield sequence can reduce the effect of field angle on MLC position and improve the delivery accuracy of IMRT plan. ADVANCES IN KNOWLEDGE: The fragmentation level of the subfield sequence may have an impact on the accuracy of the delivery of the plan. This study demonstrates this assumption by comparing the differences between 0° and actual angle verification. Mean change value (Δ) was decreased from Group A to Group B. The smaller the difference (Δ), the actual output dose of the field is more consistent with the original plan. The result of this study may help us to understand that appropriately increasing the subfield area and reducing the fragmentation level of the subfield sequence can reduce the difference between the two verification results, which can further improve the accuracy of the plan delivery in IMRT and tumor treatment.
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Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidade Modulada/normas , Desenho de Equipamento , Humanos , Tratamentos com Preservação do Órgão/métodos , Órgãos em Risco , Planejamento de Assistência ao Paciente , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/instrumentação , Radioterapia de Intensidade Modulada/métodos , Sensibilidade e EspecificidadeRESUMO
The aim of present study was to compare the dosimetric differences of the radiotherapeutic plans between synchronous and composite planning approaches in sequential intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). Twelve patients with NPC treated by sequential IMRT were enrolled. Two planning approaches were used to design sequential IMRT plan. The first was composite planning approach, in which the initial and boost plans were designed and optimized independently. The second was synchronous planning approach, in which the boost IMRT plan was designed on foundation of the initial IMRT plan, and its optimization would be adjusted based on dose distributions of the initial IMRT plan. Dosimetric comparisons in IMRT plans between composite and synchronous planning approaches were analyzed to evaluate (1) dose coverage, conformity, and homogeneity of the planning target volume (PTV), (2) sparing of organs at risk (OARs), and (3) the number of segments and monitor units (MUs). The results showed that both of the summed plans for the entire treatment course were achieved according to the original planning goals, and the dose coverage, conformity and homogeneity for each PTV was similar. With regard to sparing brain stem, spinal cord and parotid glands, there was no significant difference in the summed plans between two planning approaches. However, the boost IMRT plan by composite planning approach tended to have a higher dose coverage (P = 0.000), conformity (P = 0.000), and homogeneity (P = 0.000) than that of the plan by synchronous planning approach. Moreover, the boost plan by composite planning approach reduced the MUs significantly (P = 0.000). The results indicated that the radiotherapeutic plan by composite planning approach provides better dose coverage, conformity and homogeneity for the PTV in the boost plan than that by synchronous planning approach, and reduced MUs in sequential intensity modulated radiotherapy.