A real-world analysis of stereotactic body radiotherapy combined with immunotherapy in advanced or recurrent non-small cell lung cancer (NSCLC): A single-center experience.

Background: We aimed to assess the value of stereotactic body radiotherapy (SBRT) delivered under the situation of controlled or progressed disease during ICI therapy in advanced or recurrent NSCLC. Methods: We retrospectively collected patients with advanced or recurrent NSCLC who received SBRT concurrently with ICI in our institution between January 2017 and December 2021. Patients were divided into two groups, including those for whom SBRT was delivered initially or to the residual tumors during the first- or later-line ICI treatment (Group 1), and those for whom SBRT was given to the progressed tumors irrespective of first- or later-line ICI treatment (Group 2). Results: A total of 144 patients were included. With median follow-up duration of 25.6 (range: 3.6 to 56.2) months, median progression-free survival (PFS) was 13.7 (95 % CI: 10.4 to 17.1) months and median overall survival (OS) was 52.8 [95 % CI: 30.6 to not available (NA)] months. In Group 1 (n = 78), median PFS was 17.9 (95 % CI: 14.5 to 29.8) months while median OS was not reached and 5-year OS rate was 61.2 %. In Group 2 (n = 66), median PFS was 8.0 (95 % CI: 6.0 to 13.1) months and median OS was 30.6 (95 % CI: 21.5 to NA) months. Conclusions: SBRT combined with ICI demonstrated favorable survival for advanced or recurrent NSCLC, delivered in a controlled-disease situation as well as to progressed diseases with salvage-intent. Future prospective studies are warranted to investigate the optimal SBRT dose regimen and appropriate combination strategy to synergize ICI.

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury.

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

Combustion Characteristics of Vat-Photopolymerized Fuels with a Spiral Star Port for Hybrid Propulsion.

Despite hybrid rocket motors offering distinct advantages over solid or liquid rocket motors, their low regression rate and insufficient combustion efficiency remain significantly unimproved. This study focuses on the effects of the helix lead on the regression rate distribution and combustion efficiency of vat-polymerized fuel grains with a spiral star port for a hybrid rocket. Both experimental and numerical investigations were conducted to study the combustion characteristics and regression rate distribution of three-dimensional (3D) print grains. Spiral star grains with varying helix leads of 60, 90, and 120 mm were fabricated using light-curing 3D printing technology. A 3D simulation model was developed to obtain the temperature distribution, species mass distribution, and combustion efficiency. Furthermore, firing tests were performed on a two-dimensional radial hybrid combustion test stand to measure the regression rate. Digital image processing of computed tomography images was used to determine the regression rate. Simulation results indicated that the spiral star grain port helps to improve the combustion efficiency compared with those seen with round tube and straight star port grains. With an increase in the axial distance, the flame zone gradually shrinks, and the smaller the helix lead, the faster the shrinkage. At a mass flow rate of 1.50 g/s for oxygen, the regression rate of the spiral star grains is significantly higher than that of the straight star grain and the conventional round tubular grains, and the regression rate gradually increases with a decrease in the helix lead. This finding is expected to solve the problem of the low regression rate of solid fuels with spiral star pore-shaped grains prepared by the light-curing 3D printing method.

Inhibition of mitochondrial ROS-mediated necroptosis by Dendrobium nobile Lindl. alkaloids in carbon tetrachloride induced acute liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium nobile Lindl. (DNL) is a well-known traditional Chinese medicine that has been recorded in the Chinese Pharmacopoeia (2020 edition). The previous data showed that Dendrobium nobile Lindl. alkaloids (DNLA) protect against CCl4-induced liver damage via oxidative stress reduction and mitochondrial function improvement, yet the exact regulatory signaling pathways remain undefined. AIM OF THE STUDY: The aim of the present study was to investigate the role of necroptosis in the mode of CCl4-induced liver injury and determine whether DNLA protects against CCl4-induced acute liver injury (ALI) by inhibiting mitochondrial ROS (mtROS)-mediated necroptosis. MATERIALS AND METHODS: DNLA was extracted from DNL, and the content was determined using liquid chromatograph mass spectrometer (LC-MS). In vivo experiments were conducted in C57BL/6J mice. Animals were administrated with DNLA (20 mg/kg/day, ig) for 7 days, and then challenged with CCl4 (20 µL/kg, ip). CCl4-induced liver injury in mice was evaluated through the assessment of biochemical indicators in mouse serum and histopathological examination of hepatic tissue using hematoxylin and eosin (H&E) staining. The protein and gene expressions were determined with western blotting and quantitative real-time PCR (RT-qPCR). Reactive oxygen species (ROS) production was detected using the fluorescent probe DCFH-DA, and mitochondrial membrane potential was evaluated using a fluorescent probe JC-1. The mtROS level was assessed using a fluorescence probe MitoSOX. RESULTS: DNLA lessened CCl4-induced liver injury, evident by reduced AST and ALT levels and improved liver pathology. DNLA suppressed necroptosis by decreasing RIPK1, RIPK3, and MLKL phosphorylation, concurrently enhancing mitochondrial function. It also broke the positive feedback loop between mtROS and RIPK1/RIPK3/MLKL activation. Similar findings were observed with resveratrol and mitochondrial SOD2 overexpression, both mitigating mtROS and necroptosis. Further mechanistic studies found that DNLA inhibited the oxidation of RIPK1 and reduced its phosphorylation level, whereby lowering the phosphorylation of RIPK3 and MLKL, blocking necroptosis, and alleviating liver injury. CONCLUSIONS: This study demonstrates that DNLA inhibits the necroptosis signaling pathway by reducing mtROS mediated oxidation of RIPK1, thereby reducing the phosphorylation of RIPK1, RIPK3, and MLKL, and protecting against liver injury.

FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

PURPOSE: Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. METHODS: Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. RESULTS: Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. CONCLUSION: Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Probing the Chemistry of Sulfurous Pollutants: Accurate Thermochemistry Determination of Extensive Sulfur-Containing Species.

Sulfur-containing fuels, such as petroleum fuels, natural gas, and biofuels, produce SO2, SO3, and other highly toxic gases upon combustion, which are harmful to human health and the environment, making it essential to understand their thermochemical properties. This study used high-level quantum chemistry calculations to determine thermodynamic parameters, including entropy, enthalpy, and specific heat capacity for an extensive set of sulfur-containing species. The B3LYP/cc-pVTZ level of theory was used for geometry optimization, vibration frequency, and dihedral scan calculations. To determine an appropriate ab initio method for energy calculation, the Bland-Altman diagram, a statistical analysis method, was employed to visualize the 298 K enthalpy value between experimental data and three sets of ab initio methods: G3, CBS-QB3, and the average of G3 plus CBS-QB3. The CBS-QB3 method exhibited the highest accuracy and was eventually selected for the energy calculation in this study. Thermochemical property parameters were then calculated with the MultiWell program suite for all these sulfur-containing species, and the results were in good agreement with the thermochemical data of organic compounds and the National Institute of Standards and Technology Chemistry WebBook databases. The thermochemical property database established in this study is essential to studying sulfur-containing species in desulfurization.

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice.

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Who benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-dimensional model for candidate selection.

BACKGROUND: Despite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy. METHODS: We retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3. FINDINGS: A total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p < 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (p < 0.001). INTERPRETATION: IASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients.

Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition.

The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.

Control mechanisms of different bionic structures for hydrofoil cavitation.

Cavitation limits the efficient and stable operation of rotating machinery. The exploration of control methods for hydrofoil cavitation is important for improving the performance of hydraulic machinery. The leading-edge protuberances of the humpback flipper and the spine structure of the tail fin of sailfish are two common bionic structures for cavitation control; however, the control effects of both have limitations. Accordingly, in this study, a passive control method for hydrofoil cavitation was developed by combining the two bionic structures. With the large eddy simulation method, the cavitation processes of wavy leading-edge hydrofoil, bionic fin spine structure hydrofoil, and novel bionic combined structure hydrofoil were studied under a cavitation number of σ = 0.8. The control mechanisms of the three bionic structures for the hydrofoil cavitation were investigated. The results indicated that the novel bionic combined hydrofoil realised the superposition and complementation of the control effects of the two single bionic structures and achieved a better cavitation inhibition effect, reducing the total volume of cavitation by 43 %. In addition, it enhanced the stability of the flow field and reduced the standard deviation of the pressure coefficient on the suction surface by up to 46.55 %. This research provides theoretical support for the optimisation and modification of the blades of hydraulic machinery, such as propellers and pump turbines.

Dosiomics and radiomics improve the prediction of post-radiotherapy neutrophil-lymphocyte ratio in locally advanced non-small cell lung cancer.

PURPOSE: To develop and validate a dosiomics and radiomics model based on three-dimensional (3D) dose distribution map and computed tomography (CT) images for the prediction of the post-radiotherapy (post-RT) neutrophil-to-lymphocyte ratio (NLR). METHODS: This work retrospectively collected 242 locally advanced non-small cell lung cancer (LA-NSCLC) patients who were treated with definitive radiotherapy from 2012 to 2016. The NLR collected one month after the completion of RT was defined as the primary outcome. Clinical characteristics and two-dimensional dosimetric factors calculated from the dose-volume histogram (DVH) were included. A total of 4165 dosiomics and radiomics features were extracted from the 3D dose maps and CT images within five different anatomical regions of interest (ROIs), respectively. Then, a three-step feature selection method was proposed to progressively filter features from coarse to fine: (i) model-based ranking according to individual feature's performance, (ii) maximum relevance and minimum redundancy (mRMR), (iii) select from model based on feature importance calculated with an ensemble of several decision trees. The selected feature subsets were utilized to develop the prediction model with GBDT. All patients were divided into a development set and an independent testing set (2:1). Five-fold cross-validation was applied to the development set for both feature selection and model training procedure. Finally, a fusion model combining dosiomics, radiomics and clinical features was constructed to further improve the prediction results. The area under receiver operating characteristic curve (ROC) were used to evaluate the model performance. RESULTS: The clinical-based and DVH-based models showed limited predictive power with AUCs of 0.632 (95% CI: 0.490-0.773) and 0.634 (95% CI: 0.497-0.771), respectively, in the independent testing set. The 9 feature-based dosiomics and 3 feature-based radiomics models showed improved AUCs of 0.738 (95% CI: 0.628-0.849) and 0.689 (95% CI: 0.566-0.813), respectively. The dosiomics & radiomics & clinical fusion model further improved the model's generalization ability with an AUC of 0.765 (95% CI: 0.656-0.874). CONCLUSIONS: Dosiomics and radiomics can benefit the prediction of post-RT NLR of LA-NSCLC patients. This can provide a reference for evaluating radiotherapy-related inflammation.

Mitochondrial Regulation of Macrophages in Innate Immunity and Diverse Roles of Macrophages During Cochlear Inflammation.

Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation. Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases, including cochlear inflammation. The distribution, number, and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions, including noise exposure, ototoxicity, and age-related degeneration. However, the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear. Here, we summarize the major factors and mitochondrial signaling pathways (e.g., metabolism, mitochondrial reactive oxygen species, mitochondrial DNA, and the inflammasome) that influence macrophage activation in the innate immune response. In particular, we focus on the properties of cochlear macrophages, activated signaling pathways, and the secretion of inflammatory cytokines after acoustic injury. We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.

Moving beyond cisplatin resistance: mechanisms, challenges, and prospects for overcoming recurrence in clinical cancer therapy.

Cisplatin, a classical platinum-based chemotherapy agent, has been a frontline treatment for various cancers for decades. However, its effectiveness has been hindered by the development of resistance, leading to cancer relapse. Addressing this challenge is crucial for both clinical practice and research. Hence, the imperative to unravel the intricate mechanisms underpinning cisplatin resistance and to uncover novel strategies to overcome this barrier holds immense significance. Within this review, we summarized the classification of platinum agents, highlighting their roles in therapeutic landscapes. We discussed the diverse mechanisms behind cisplatin resistance, including diminished intracellular cisplatin accumulation, intracellular detoxification, DNA repair, autophagy responses, heat shock proteins, tumor microenvironment, cancer stem cells, epigenetic regulation, ferroptosis resistance, and metabolic reprogramming. Drawing from this comprehensive understanding, we offered a series of prospective solutions to surmount cisplatin resistance and consequently mitigate the specter of disease recurrence within the realm of clinical cancer therapy.

SIRT3-Mediated Deacetylation of SDHA Rescues Mitochondrial Bioenergetics Contributing to Neuroprotection in Rotenone-Induced PD Models.

Mitochondrial dysfunction is critically involved in the degeneration of dopamine (DA) neurons in the substantia nigra, a common pathological feature of Parkinson's disease (PD). Previous studies have demonstrated that the NAD+-dependent acetylase Sirtuin 3 (SIRT3) participates in maintaining mitochondrial function and is downregulated in aging-related neurodegenerative disorders. The exact mechanism of action of SIRT3 on mitochondrial bioenergetics in PD pathogenesis, however, has not been fully described. In this study, we investigated the regulatory role of SIRT3-mediated deacetylation of mitochondrial complex II (succinate dehydrogenase) subunit A (SDHA) and its effect on neuronal cell survival in rotenone (ROT)-induced rat and differentiated MN9D cell models. The results revealed that SIRT3 activity was suppressed in both in vivo and in vitro PD models. Accompanying this downregulation of SIRT3 was the hyperacetylation of SDHA, impaired activity of mitochondrial complex II, and decreased ATP production. It was found that the inhibition of SIRT3 activity was attributed to a reduction in the NAD+/NADH ratio caused by ROT-induced inhibition of mitochondrial complex I. Activation of SIRT3 by icariin and honokiol inhibited SDHA hyperacetylation and increased complex II activity, leading to increased ATP production and protection against ROT-induced neuronal damage. Furthermore, overexpression of SDHA also exerted potent protective benefits in cells treated with ROT. In addition, treatment of MN9D cells with the NAD+ precursor nicotinamide mononucleotide increased SIRT3 activity and complex II activity and promoted the survival of cells exposed to ROT. These findings unravel a regulatory SIRT3-SDHA axis, which may be closely related to PD pathology. Bioenergetic rescue through SIRT3 activation-dependent improvement of mitochondrial complex II activity may provide an effective strategy for protection from neurodegeneration.

Gss deficiency causes age-related fertility impairment via ROS-triggered ferroptosis in the testes of mice.

Glutathione synthetase (GSS) catalyzes the final step in the synthesis of glutathione (GSH), a well-established antioxidant. Research on the specific roles of the Gss gene during spermatogenesis remains limited due to the intricate structure of testis. In this study, we identified pachytene spermatocytes as the primary site of GSS expression and generated a mouse model with postnatal deletion of Gss using Stra8-Cre (S8) to investigate the role of GSS in germ cells. The impact of Gss knockout on reducing male fertility is age-dependent and caused by ferroptosis in the testis. The 2-month-old S8/Gss-/- male mice exhibited normal fertility, due to a compensatory increase in GPX4, which prevented the accumulation of ROS. With aging, there was a decline in GPX4 and an increase in ALOX15 levels observed in 8-month-old S8/Gss-/- mice, resulting in the accumulation of ROS, lipid peroxidation, and ultimately testicular ferroptosis. We found that testicular ferroptosis did not affect spermatogonia, but caused meiosis disruption and acrosome heterotopia. Then the resulting aberrant sperm showed lower concentration and abnormal morphology, leading to reduced fertility. Furthermore, these injuries could be functionally rescued by inhibiting ferroptosis through intraperitoneal injection of GSH or Fer-1. In summary, Gss in germ cells play a crucial role in the resistance to oxidative stress injury in aged mice. Our findings deepen the understanding of ferroptosis during spermatogenesis and suggest that inhibiting ferroptosis may be a potential strategy for the treatment of male infertility.

AS-NeSt: A Novel 3D Deep Learning Model for Radiation Therapy Dose Distribution Prediction in Esophageal Cancer Treatment With Multiple Prescriptions.

PURPOSE: Implementing artificial intelligence technologies allows for the accurate prediction of radiation therapy dose distributions, enhancing treatment planning efficiency. However, esophageal cancers present unique challenges because of tumor complexity and diverse prescription types. Additionally, limited data availability hampers the effectiveness of existing artificial intelligence models. This study developed a deep learning model, trained on a diverse data set of esophageal cancer prescriptions, to improve dose prediction accuracy. METHODS AND MATERIALS: We retrospectively collected data from 530 patients with esophageal cancer, including single-target and simultaneous integrated boost prescriptions, for model building. The proposed Asymmetric ResNeSt (AS-NeSt) model features novel 3-dimensional (3D) ResNeSt blocks and an asymmetrical architecture. We constructed a loss function targeting global and local doses and validated the model's performance against existing alternatives. Model-assisted experiments were used to validate its clinical benefits. RESULTS: The AS-NeSt model maintained an absolute prediction error below 5% for each dosimetric metric. The average Dice similarity coefficient for isodose volumes was 0.93. The model achieved an average relative prediction error of 2.02%, statistically lower than Hierarchically Densely Connected U-net (4.17%), DoseNet (2.35%), and Densely Connected Network (3.65%). It also demonstrated significantly fewer parameters and shorter prediction times. Clinically, the AS-NeSt model raised physicians' ability to accurately preassess appropriate treatment methods before planning from 95.24% to 100%, reduced planning time by over 61% for junior dosimetrists and 52% for senior dosimetrists, and decreased both inter- and intra-dosimetrist discrepancies by more than 50%. CONCLUSIONS: The AS-NeSt model, developed with innovative 3D ResNeSt blocks and an asymmetrical encoder-decoder structure, has been validated using clinical esophageal cancer patient data. It accurately predicts 3D dose distributions for various prescriptions, including simultaneous integrated boost, showing potential to improve the management of esophageal cancer treatment in a clinical setting.

Electrochemiluminescence Properties and Sensing Application of Zn(II)-Metal-Organic Frameworks Constructed by Mixed Ligands of Para Dicarboxylic Acids and 1,10-Phenanthroline.

Four metal-organic frameworks (MOFs) were designed and prepared through a mixed-ligand strategy by controlling the combination of various dicarboxylic acid ligands with invariant center metal and o-phenanthroline heterocyclic ligand. The regulatory effects of ligand electronic band and crystal structure on the electrochemiluminescence (ECL) characteristics of MOFs were verified by experimental results and density functional theory (DFT) calculations. The flexible chain structure of MOF-2 promotes electron transfer between MOF electroactive free radicals and the co-reactant, making it show outstanding ECL characteristics among all of the four MOFs with the luminescence quantum efficiency 8.37 times that of tris(bipyridine)-ruthenium(II) ([Ru(bpy)3]2+). Meanwhile, a new ECL mechanism for MOF luminescent crystal materials with reactive oxygen species in solvents as a co-reactant in the aqueous aerobic environment has been proposed. MOF-2 was selected to construct an ECL sensor for the determination of glucose in human urine samples. This study provides a useful idea for the development and design of new luminescent molecular crystal materials.

Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).

This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

Study on Mechanical Properties and Failure Mechanisms of Highly Filled Hydroxy-Terminated Polybutadiene Propellant under Different Tensile Loading Conditions.

To study the mechanical properties of highly filled hydroxy-terminated polybutadiene (HTPB) propellant with 90 wt% solid fillers, the stress-strain curves of the propellant under different temperatures (-50 to 70 °C) and strain rates (0.000476 to 0.119048 s-1) were obtained by uniaxial tensile test. Moreover, to obtain the glass transition temperature and understand the effect of low temperatures on the mechanical properties of the propellant, DMA experiments were carried out. On this basis, the mechanical response laws of the propellant were analyzed, and the master curves of mechanical properties were established. Furthermore, the fracture features of the propellant under typical loading conditions were obtained by SEM, and the corresponding failure mechanisms were analyzed. The results show that the maximum strength decreases with increasing temperature, while the maximum elongation increases with increasing temperature at the same strain rate. The maximum tensile strength increases with increasing strain rate, while the maximum elongation decreases with increasing strain rate at the same temperature. The maximum tensile strength is lowest with a value of 0.35 MPa when the temperature is 343.15 K and the strain rate is 0.000476 s-1, at which time the maximum elongation reaches the highest with a value of 44%. In terms of failure mechanisms, the propellant shows no particle fracture, and the failure modes of the propellant are mainly matrix tearing and dewetting.